AJH
1990;
3:137S-U6S
Calcium and Blood Pressure
An Epidemiologic Perspective Jeffrey A. Cutler and Erica Brittain
C
alcium intake merits serious consideration among the environmental and lifestyle factors that may be important in the etiology of primary hypertension. Ever since reports appeared relating drinking water hardness to cardiovascular mortality, epidemiologists have been interested in the relationship of divalent cations, especially calcium and magnesium, to blood pressure ( B P ) . Research findings in humans now include data on physiologic and pathophysiologic relationships; observational epidemiologic studies, both of calcium in body fluids and in the diet; and clinical trials. This review focuses on the 1-3
blood pressure; in two trials, both systolic and diastolic pressure were significantly reduced; and in the remainder results were equivocal. Pooled analyses yielded estimates of a small (1.8 mm Hg), significant reduction in systolic blood pressure, but no effect on diastolic pressure. Epidemiologic relationships with serum and urinary calcium, and the possible mechanisms of these effects, are also discussed. We conclude that the evidence from studies in humans is suggestive, but not conclusive, regarding a role for calcium in hypertension. Recommendations for further epidemiologic studies are presented. Am J Hypertens 1990;3:137S-146S
KEY WORDS:
Epidemiology, calcium, hypertension.
latter two areas, in that alteration of dietary intake would potentially be a most attractive strategy for treatment or prevention of hypertension. CONCEPTUAL AND METHODOLOGIC CONSIDERATIONS Drawing inferences from available epidemiologic studies should be facilitated by a clear understanding of the underlying research strategies and methodologic approaches. Epidemiology is guided by the goal of establishing etiologic relationships between external causes and biologic effects (usually, diseases). In pursuing this goal, a set of causal criteria have evolved, formulated in various ways and criticized by some, but generally including the following seven items: 4
From the Prevention and Demonstration Research Branch (JAC) and Biostatistics Research Branch (EB), Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland. Address correspondence to Jeffrey A. Cutler, MD, Room 604, Federal Building, National Institutes of Health, Bethesda, MD 20892.
existence and strength of statistical association between the putative cause and its effect; specificity of the association; consistency of the association; 0895-7061/90/$0.00
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We reviewed the research literature on the epidemiologic relationship between blood pressure levels and calcium, with an emphasis on dietary intake. A conceptual framework for causal inference is summarized; then the designs and results of observational and intervention studies are presented. Of 25 reports of observational studies relating intake of calcium or calcium-rich foods to blood pressure, the majority found some evidence of an inverse association. However, many analyses did not support this relationship, and only two studies have confirmed the inverse association with a prospective design. Nineteen randomized controlled clinical trials of calcium supplementation have been reported, excluding those exclusively in pregnant women. Eleven of these showed no significant effects on
dose-response relationship; time order (effect follows cause); response to experimental manipulation; and plausible biologic mechanism. These criteria require some elaboration, particularly as they apply to the calcium blood pressure hypothesis.
Specificity and Confounding Variables that are associated both with the cause and the effect must be controlled either in the design or the analysis, to be certain that the primary association is specific. The traditional techniques are matching and stratification (subgrouping). However, for more than a few covariates—usually the situation with BP studies—multiple adjustment techniques using statistical models are more powerful. Use of these models with nutrient data focuses attention on the problem of multicolinearity, ie, the high intercorrelations of intakes of certain nutrients. Another pitfall of complex multivariate models is overadjustment, by which is meant removing an apparent effect of a factor by including in the model an intervening variable related to the mechanism; a possible example is including both dietary and serum calcium. 5
Consistency of Associations This refers simply to whether an association is found repeatedly in different studies of similar populations, and to some extent, in diverse populations. The latter can be examined among strata of a single study as well. However, distinguishing between real and chance differences in the association among study populations and subgroups is difficult, and is facilitated by clear prior hypotheses about such variability. Dose-Response Gradations of effect depending in a regular manner upon levels of the exposure to the tested compound, in this case dietary calcium, strengthens a causal inference. A useful approach is classifying intake into quantiles (eg, deciles), and examining mean BP across these strata. Time Order Most of the observational epidemiologic studies of calcium and BP have been crosssectional, a design which cannot establish whether diet has determined current BP levels, or, for example, diet changes
Intervention Studies Properly conducted clinical trials can overcome many of the problems in interpreting nonexperimental epidemiologic data, including time order and various other sources of confounding. Indeed, clinical trials provide the strongest type of evidence both for causality and for the ability to affect the disease or condition to the benefit of patients or healthy individuals. Among the limitations of trials, however, is the uncertainty about the necessary length of follow-up to allow sufficient time for a biologic effect. Most trials of calcium supplementation have lasted a few weeks or months. Also, trials should have one or more primary hypotheses stated a priori, including the outcome variable, as well as which data points of the multiple measurements of the variable will be used and how the data will be analyzed, to ensure proper and unbiased use of significance testing at the conclusion. Biologic Mechanisms Knowledge of physiologic, cellular and molecular mechanisms gained from human and animal experimentation can lend much weight to epidemiologic conclusions, but a complete theory of the chain of events is not required for useful application of epidemiologic evidence. OBSERVATIONAL STUDIES ON DIETARY CALCIUM We have reviewed 25 reports of studies conducted in 17 populations, not including subsets (Table l ) . Ten of the populations are from US states and territories, 6 from Western Europe, and 1 from South Africa. There are 2 reports from the Western Electric Study (Chicago), 4 papers from the Honolulu Heart Program (Japanese men living in Hawaii), and 6 from the US National Health and Nutrition Examination Surveys (NHANESI and II). Most subjects have been adults; most studies included both sexes, and some included blacks. Regarding design, all but 1 have been basically crosssectional; three had a longitudinal component as well, but 1 of them did not include milk intake as a variable, since it did not have an independent effect crosssectionally. The sample sizes ranged from 100 in a few studies to around 58,000 in the Nurses' Health Study. In their designs or analyses most studies controlled for effects of age, race, sex and body weight. Otherwise, adjustment for other potential confounders was highly variable, as indicated in Table 1. A particular methodologic issue in these studies is the method of dietary data collection. Any method is subject to recall and reporting errors, and sbme bias is likely if the specific purpose of the study is known to subjects and/or research staff. However, an intent to evaluate the role of calcium intake appears to not have been obvious in most of the studies. Most of the studies 5 - 2 8
13
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Measures of Association Most commonly cited are the relative risk (or odds ratios) for a disease (ie, hypertension) or the regression/correlation coefficient, for a continuous variable (ie, BP), the latter usually being the more sensitive measure. Either (including standardized coefficients) can be used for statistical significance testing and expression of the result, but for interpreting the medical significance, unstandardized coefficients or relative risks are needed, and are cited in this review whenever available. Relative risks of 1.5 or greater are often considered important effect sizes for knowledge and action.
have been made in response to knowledge of BP levels. More longitudinal studies are needed.
TABLE 1. OBSERVATIONAL STUDIES OF DIETARY CALCIUM AND BLOOD PRESSURE: DESIGN FEATURES
Langford 1973 McCarron 1982
Mississippi blacks Oregon
6
7
Ackley 1983 Garcia-Palmieri 1984 Connor 1984 Nichaman 1984 Zhang 1988
California whites Puerto Rico Oregon Chicago whites Same as above
8
9
10
11
12
Hawaii, Japanese-Americans Same as above Same as above US black/white from NHANES I
13
5
14
15
Harlan 1984A Harlan 1984B Gruchow 1985 Harlan 1985 Sempos 1986 Kromhout 1985 Sowers 1985 Kok 1986 Steyn 1986
16
17
18
same, NHANES I same, NHANES II same, NHANES I/II Zutphen Iowa Amsterdam South Africa, "col ored" Wales Denmark Italy US nurses
19
21
20
22
23
25
24
Elliott 1987 Thomson 1987 Trevisan 1988 Witteman 1989
Study design
School girls 35 M, mean = 42 55 F, mean = 39 MF, 3 0 - 7 9 M, 4 5 - 6 4 MF, 16-65 M, 4 0 - 5 5 Same as above
X-sect case-control
55 46u44 5,050/541 Mf 7,932 407 1,976/1,014 1,884/1,450
M, 4 5 - 6 4 Same as above Same as above Same as above MF, 18-74
X-sect X-sect X-sect X-sect/prosp Same as above X-sect/prosp X-sect X-sect X-sect X-sect
MF, 2 5 - 7 4 MF, 2 5 - 7 4 MF, 18-74 MF, 2 1 - 7 4 MF, 4 0 - 7 4 M, 4 0 - 5 9 F, 2 0 - 3 5 , 5 5 - 8 0 MF, 4 0 - 6 5 MF, 15-64
X-sect X-sect X-sect X-sect X-sect X-sect/prosp X-sect X-sect X-sect
J HR,SES, 2,055 I [serum Ca,P, AAT,+ 5,468 J 9,555 Not sex 5,305 Alcblood Pb,+ 5,840/5,490 794/605/498}: Cal,alc,K 86/222 Ale 2,291 cal,alc,HR,+ 976 Race only
26
27
M, 4 5 - 4 9 F, mean = 50 MF, 2 0 - 5 9 F, 30-55
X-sect X-sect X-sect Prosp
356 103 4,354 58,218
28
29
Sample size
8,006/6,858 6,496 615 7,011 10,732
Covariates controlled* Not body weight Body weight "com parable" Alct Alc,Hr,educ,+ Alc,SES,fatty acids Ale Alc,HR,FH,+ Alc,PA,K Alc,K Body weight
Ale Alc,fatty foods Alc,K,Mg,fiber
* In addition to age, sex, race, and body weight, j Subset, χ Number at successive exams. Abbreviations: ATT = aspartate amino-transferase, Ale = alcohol, Ca = calcium, Cal = calories, educ = education, F — females, PH = family his tory, HR = heart rate, Κ = potassium, Μ = males, NHANES = National Health and Nutrition Examination Survey, Ρ = phosphorous, PA = physical activity, Pb = lead, prosp = prospective, SES = socioeconomic status, WT = weight, X-sect = cross-sectional, + = additional covariates.
have used the 24 h recall as their main instru ment 5,7-10,13,14,16-21,23,24 t h o d has satisfactory precision for groups of people, but in correlation/regression analyses, in which individuals are the units of analysis, random day-to-day variation tends to produce false negative results. Five of the studies relied on a variety of food-frequency questionnaires, aimed at usual intake. ' ' ' Some examples of this kind of questionnaire have been shown to provide estimates of calcium intake that correlate well with more laborious diet histories. The Western Electric study ' used an in-depth "reference standard" method for obtaining a four week diet history, and the Caerphilly Heart Study used a seven day weighted dietary record. The first report of a calcium-blood pressure associa tion was apparently Langford's description of a low cal cium intake, and a low urinary ratio of sodium to cal cium, in black schoolgirls with high systolic BP (SBP) levels. No details of this study have been published. Next, McCarron's case-control study, comparing agem e
15
30
22
25,27
28
11 12
26
6
sex-race matched hypertensives and normotensive vol unteers, found a significantly lower intake of calcium from food in the former, mostly of nonmilk dairy prod ucts. There were no differences in intake of calories, sodium, or potassium, nor (it was stated) in body weight. A crude relative odds for hypertension ( < 1 g calcium ν > 1 g) can be calculated as 3.2, but it should be em phasized that this is without adjustment for other risk factors, including alcohol intake. In the Rancho Bernardo cohort, Ackley found an in verse relationship with milk intake in men, significant for diastolic but not systolic BP, but no such relationship in women. In a subset of 541 men with 24 h recall data, diastolic BP (DBP) was also associated inversely with total food calcium, while SBP was associated inversely with milk calcium; these analyses were controlled for alcohol intake. Another report of mostly positive results for men came from the Puerto Rico Heart Study, which described numerous analyses, all stratified by age and urban-rural residence and adjusted for a number of im7
8
9
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Reed 1982 Reed 1985 Joffres 1987 Criqui 1989 McCarron 1984
Gender, age (years)
Region, race (if given)
Author, year
10
11
11
12
13
5
14
for magnesium and for potassium. In each case the highest quartile was lower by about 5 to 6 mm Hg systolic, and 2 to 3 mm Hg diastolic, than the lowest quartile. Most recently, Criqui evaluated the separate and combined effects of calcium, potassium and alcohol intake. Calcium was inversely related to systolic and diastolic BP only in nondrinkers and light drinkers. The absence of an association among moderate to heavy drinkers led the authors to suggest that malabsorption of calcium might explain a small part of the large hypertensive effect of alcohol. Two large data sets on this topic come from the two National Health and Nutrition Examination Surveys (NHANES). There have been five reports on calcium and BP from NHANES I (1971 to 1974) on different but overlapping subsets of the s a m p l e , and two from NHANES II (1976 to 1 9 8 0 ) . ' Subject-related exclusion differed somewhat, but most of the differences were based on availability of biochemical measures on subsamples. For the most part, analyses were based on a single 24 h recall. Categorical analyses used various definitions of hypertension as the response variable. In NHANES I, McCarron found a significant inverse association with systolic hypertension, but various aspects of the analysis, including adequacy of adjustment for body mass, have been questioned. ' In NHANES II, Harlan found inverse associations of both diastolic hypertension and isolated systolic hypertension with frequency of calcium-rich foods in three of four age-sex strata, but without control for any covariates. Analyses using continuous BP are probably more informative, and findings have been inconsistent. In NHANES I, McCarron reported a correlation coefficient between calcium intake and SBP of — 0.6, uncontrolled for any confounders. Harlan, stratifying by sex and race (four groups), found four significant associations between calcium intake and SBP or DBP among the eight examined, two direct and two inverse; the latter were in blacks and women. He adjusted for many potential confounders; in fact, including serum calcium could be considered overadjustment. In a later report without race stratification, an inverse association was found only for SBP in older women. Gruchow reported no overall association with SBP in his unstratified analysis, adjusting for age, race, and body mass. In probably the most straightforward analyses, Sempos examined mean BPs by quintile of calcium intake for four sex-race strata, excluding subjects under age 40, and found significant inverse association only for black men, with strong similar trends for black women. He described similar results for NHANES II especially in black women, but none of the associations was significant, perhaps because the number of blacks was substantially less. Sempos's analyses were adjusted for age and body mass, but not for alcohol intake. Harlan's findings for NHANES II are not directly comparable, because they were not race-stratified, but are consistent in that an 15
16-20
20
21
16
30 31
21
16
17
18
19
20
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portant covariates (Table 1). The associations were mainly between SBP and milk or milk calcium intake, and were significant in each stratum except young rural men. The size of the effect was about 0.5 mm Hg per 4 oz milk. In the urban strata a dose-response relationship was apparent, with a relative risk for hypertension of about two, comparing no milk intake with 32 oz/day. Conner sampled families and reported diet-blood pressure relationships separately for male and female spouses. In this small study correlation coefficients were mostly positive (ie, greater calcium intake, higher BP levels), but only for SBP in men was this significant. Alcohol intake was not controlled in the analysis. The first report of a prospective analysis came as an abstract from the Western Electric study, later extended in another abstract (Ref. 12, and personal communication). As in most of the previous studies, an inverse relationship was found crosssectionally in these white men, for both SBP and DBP, with adjustment for the main covariates. However, results of the prospective analyses were inconsistent: Nichaman found no association between baseline calcium and eight year incidence of one or more measurements of DBP ^ 9 5 mm Hg, while Zhang reported an inverse relationship for onset of relatively severe DBP elevations, but not for less extreme levels, and no association with incidence of systolic hypertension, during seven years of follow-up. The four reports from the Honolulu Heart Program represented important further explorations of a calcium-blood pressure relationship. Reed's first paper presented analyses excluding only men on antihypertensive drugs and found significant inverse associations at the baseline exam between milk intake and both SBP and DBP, adjusting for age and body mass. However, the associations were lost when 8 to 11 other variables, including alcohol, heart rate, and family history of hypertension, were added in multiple regression analyses. Therefore, milk intake was not included in the six year prospective analysis of BP change. In the next paper men on a special diet, and those with cardiovascular disease, were excluded, and calcium from food, primarily dairy, was highly associated with SBP and DBP, even controlling for alcohol and physical activity. The contrast between the two analyses could be explained if family history, milk (dairy calcium) intake, and sympathetic activity (heart rate) were all involved in a single causal chain. In the second analysis, potassium and calcium intake were found to be highly correlated, and with both in the regression, calcium was no longer related to BP. Reed pointed to this as an example of the problem of multicolinearity, and the need for intervention trials for resolution. Subsequently, Joffres reported findings from a subset reexamined during 1970 to 1972, which reinforced the point about specificity in a different way: the significant associations (age- and body mass-adjusted) between BP and food calcium were very similar in magnitude and direction to those
21
22
23
24
25
26
27
28
29
It would be very difficult to summarize these studies quantitatively, because of variations in methodology. Although a simple count of studies or strata within stud ies indicates somewhat more positive than negative results regarding an inverse association, there is consid erable inconsistency. There are several possible explana tions. A few analyses have not controlled adequately for
powerful confounding variables, such as obesity and alcohol intake; both these factors would probably tend to produce spurious associations between low calcium intake and higher BP in crosssectional studies. On the other hand, as Sempos has pointed out, large day-to day variability of calcium intake for individuals, com pared to variation among individuals, would tend to lead to false negative results. Also, several of the nega tive studies have had the smallest sample s i z e s . ' ' When results are inconsistent, true heterogeneity of effect among subgroups is a possibility, but except per haps for blacks in NHANES, there is little indication of demographic variation (age, sex, etc). A more biologi cally grounded hypothesis would be a nonlinear rela tionship, such that an effect is more apparent when calcium intake is low. However, that does not seem to explain many of the differences among populations, eg, an effect was found in Puerto Rican men, who had relatively high intake (about 1 g), while an effect was more apparent in black men in NHANES I than in white women, even though the latter had lower estimated intake (601 ν 722 mg/day). Other possible effect modifi ers that have been suggested include vitamin D, men tioned above, and dietary sodium intake. 20
10
23
23
26,27
32
RANDOMIZED TRIALS OF CALCIUM SUPPLEMENTATION As stated above, randomized clinical trials testing the effect of oral calcium salts on BP change provide data that overcome many of the problems of observational studies. Table 2 summarizes design features and the results of 19 trials reported between 1983 and 1989 27,33-50 (Using a variety of search techniques, in cluding a computerized literature search, we have iden tified no additional randomized trials through October 1989). As there is another paper in this symposium that discusses the intervention studies in detail, this review is brief. Several trials conducted during pregnancy are ex cluded. Nine of the trials studied nonhypertensive sub jects, exclusively in seven of t h e s e . ' The groups ranged from young adults, to postmenopausal wo men. Three included both sexes, three studied men only, and three women only. Most of the trials were double-blind. (Only the test of calcium-enriched yeast was blind in Vinson's study. ) Six had parallel group designs, with sample sizes ranging from 14 to 8127,33,35,37-39; fa three with crossover designs had 7, 32, and 50 subjects each. ' ' Intervention and followup lasted from six weeks to four years, with a median of eight weeks. The dose of elemental calcium was 0.5 to 2 g; seven trials used 1.0 to 1.5 g. The calcium was ad ministered as tablets containing either a single calcium salt, or a combination of two compounds, except for one dietary trial and the yeast arm of Vinson's trial. For primary results of each trial we used changes through end of follow-up in seated (or if not given, 27
33-40
33
27
39
e
34
37
36
40
39
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inverse association was found for all women combined, with adjustment for alcohol intake, blood lead, and other covariates. Eight other studies, including five from Western Eu rope, have been published in the past five years, with mixed results. Using a diet history to estimate calcium from food over a 6 to 12 month period, Kromhout found significant inverse relationships with SBP and DBP in the Zutphen cohort at the 1965 and 1970 exams, but not at the 1960 exam. Potassium intake was in cluded in the analyses. However, changes in calcium intake were not related to changes in BP in these men over either five year period. Sowers included calcium from diet supplements and drinking water in her esti mates of intake, and found only weak nonsignificant inverse associations with SBP, in both younger and older women. A subgroup analysis did suggest in creased SBP in those with both low calcium and low vitamin D. Steyn reported univariate inverse associa tions of hypertension with intakes of calcium, as well as potassium, magnesium, and saturated fat, but no data were presented. Kok used a food frequency question naire to estimate calcium over a one week period, and found significant inverse relationships except with DBP in men, adjusting for most confounders but not other micronutrients. Elliott based estimates of dietary in take on carefully recorded seven day food records, but found no associations of BP or hypertension with any nutrients except protein intake, in middle-aged men not on antihypertensive medication. Thomsen divided a small sample of postmenopausal women by tertiles of calcium intake, and found no differences in SBP or DBP among them. Trevisan related frequency of consum ing various calcium-rich foods to BP levels, and found significant inverse associations mainly between whole milk and systolic BP. Coefficients had the opposite (posi tive) sign for skim milk, perhaps because those with higher BP were attempting to reduce cardiovascular risk by lowering dietary fat. Finally, the only purely prospec tive study of dietary factors, including calcium, in rela tion to BP was the Nurses's Health Study, reported in 1989. It supported the results of many of the crosssectional studies by showing that over a four year period the relative risk of self-reported hypertension for a cal cium intake greater than or equal to the current Recom mended Daily Allowance, 800 mg/day, was 0.78 (sta tistically significant in this large cohort) when compared with an intake of less than 400 mg/day. These analyses were controlled for intake of alcohol, magnesium, potas sium and fiber.
TABLE 2. RANDOMIZED TRIALS OF CALCIUM SUPPLEMENTATION
Belizan 1 9 8 3
Dose (g)
SBP (P)**
DBP (P)
18-35 MF ?age Μ 35-65 F 35-65 F 21-70 MF, W(B) 21-70 MF, W(B) 21-75 MF, BW 16-29 M(F) 43 mean MF 18-75 F(M), B(W) 43 mean M(F) 58 mean M(F) 20-23 F 49 mean MF, BW 48 mean MF 19-52 M, W(B)
Parallel DB, plac X-over plac Parallel DB, plac Parallel DB, plac X-over DB, plac X-over DB, plac X-over DB, plac Parallel DB, plac X-over DB, plac Parallel DB, plac X-over DB, plac Parallel DB, plac Parallel DB, plac X-over DB, plac X-over DB, plac Parallel DB, plac
57
22 wks
1.0
7
6 wks
1.0
F:-2(.01) M: —1(.35) + 5(NS)
-4(.0001) -6(.0001) + 2(NS)
Sunderrajan 1 9 8 4
81
4 yrs
1.5
+ 2(NS)
+ 2(NS)
34
4 yrs
1.5
-20(.06)
-l(NS)
32
8 wks
1.0
-2(NS)
-3(.05)
48
8 wks
1.0
-4(.02)
0(NS)
17
8 wks
0.8
90
12 wks
1.0
17
15 wks
1.0
32
4 wks
1.5
21
8 wks
1.0
+ 4(NS)
+ 2(NS)
47
2 mos
58
6 wks
0.4 0.8 1.5
-4(NS) + 1(NS) -1.7(NS)
+ 1(NS) 0(NS) + 0.4(NS)
18
4 wks
0.4
+ 4(NS)
+ 1(NS)
18
5 days
1.0
-5(.05)
0(NS)
75
12 wks
1.5
Ν
postmenopausal
28
lyr
2.0
Ν
19-24 Μ
14
7 wks
0.5 (glucose) 0.5(yeast)
+ 7.0(7) + 7.4(NS)
0(NS) -5.3(.01)
Ν
21-65 MF 41 mean M(F) 39-67 M(F)
Parallel DB, plac Parallel BP/open (see text) X-over open X-over
50
8 wks
1.15 (diet)
-2(.02)
-l(NS)
14
4 wks
1.0
+ 2(NS)
+ 0.7(NS)
27
1 wk
2.16
-10.4
-2.3
Ν
34
Ν
35
Η McCarron 1 9 8 5
Ν
36
Η Meese 1 9 8 6
Η
41
Grobbee 1 9 8 6
Η
42
Strazzullo 1 9 8 6
Bloomfield 1 9 8 6 Zoccali 1 9 8 6
Η
43
Η
44
Η
45
Nowson 1 9 8 6
Η
46
Van Beresteyn 1 9 8 6
37
Ν
Capuccio 1 9 8 7
47
Η
Lasaridas 1 9 8 7
48
Η
Lyle 1 9 8 7
Ν
38
Thomsen 1 9 8 7 Vinson 19 8 7
27
39
Bierenbaum 1 9 8 8
40
Siani 1 9 8 8
49
Η
Saito 1 9 8 9
50
Η
Parallel DB, plac
No effect -2(.ll)
-0(NS) -2(NS)
-l(NS)
No effect
W:-4 -1 B:-7 -1 (P = .01, races combined) -4(NS) 0(NS)
(P = .01 for mean BP) * A negative sign indicates treatment group reduced more than control group. ** The Ρ value reflects the main analysis done by the authors. Abbreviations: Β = blacks, BP = blood pressure, DB = double-blind, F = females, Η = hypertensive, Μ = males, Ν = normotensive, NS = nonsignificant, plac = placebo, W = whites, X-over = crossover.
supine) SBP and DBP. Of the nine trials, t w o had positive results, ie, SBP and DBP were significantly re duced (except SBP in males in Belizan ); four had nega tive results ' ' ' (a nonsignificant rise in BP in two studies); and three had mixed results. Among the latter an effect was seen for SBP or DBP, but not both, in t w o ' ; in the third an effect on SBP only was seen for calcium yeast, but not for calcium gluconate. In order to provide a more powerful test of the hy pothesis and a more quantitative summary of these 3338
33
27 34 35 37
36
40
39
trials, we have pooled the observed BP changes, weighting each trial, or stratum within the trial, by the inverse variance of the treatment effect, ie, for both SBP and DBP, the mean change in the treatment group minus mean change in the control group (see Appen dix). The resulting pooled estimates and 9 5 % confi dence limits were as follows: SBP, —1.3 mm Hg (—3.2, + 0.8), and DBP - 1 . 3 ( - 2 . 6 , - 0 . 1 ) . Thus, only the dia stolic effect was marginally significant, ie, a two-sided P
1990;
3:137S-U6S
Calcium and Blood Pressure
An Epidemiologic Perspective Jeffrey A. Cutler and Erica Brittain
C
alcium intake merits serious consideration among the environmental and lifestyle factors that may be important in the etiology of primary hypertension. Ever since reports appeared relating drinking water hardness to cardiovascular mortality, epidemiologists have been interested in the relationship of divalent cations, especially calcium and magnesium, to blood pressure ( B P ) . Research findings in humans now include data on physiologic and pathophysiologic relationships; observational epidemiologic studies, both of calcium in body fluids and in the diet; and clinical trials. This review focuses on the 1-3
blood pressure; in two trials, both systolic and diastolic pressure were significantly reduced; and in the remainder results were equivocal. Pooled analyses yielded estimates of a small (1.8 mm Hg), significant reduction in systolic blood pressure, but no effect on diastolic pressure. Epidemiologic relationships with serum and urinary calcium, and the possible mechanisms of these effects, are also discussed. We conclude that the evidence from studies in humans is suggestive, but not conclusive, regarding a role for calcium in hypertension. Recommendations for further epidemiologic studies are presented. Am J Hypertens 1990;3:137S-146S
KEY WORDS:
Epidemiology, calcium, hypertension.
latter two areas, in that alteration of dietary intake would potentially be a most attractive strategy for treatment or prevention of hypertension. CONCEPTUAL AND METHODOLOGIC CONSIDERATIONS Drawing inferences from available epidemiologic studies should be facilitated by a clear understanding of the underlying research strategies and methodologic approaches. Epidemiology is guided by the goal of establishing etiologic relationships between external causes and biologic effects (usually, diseases). In pursuing this goal, a set of causal criteria have evolved, formulated in various ways and criticized by some, but generally including the following seven items: 4
From the Prevention and Demonstration Research Branch (JAC) and Biostatistics Research Branch (EB), Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland. Address correspondence to Jeffrey A. Cutler, MD, Room 604, Federal Building, National Institutes of Health, Bethesda, MD 20892.
existence and strength of statistical association between the putative cause and its effect; specificity of the association; consistency of the association; 0895-7061/90/$0.00
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on September 12, 2015
We reviewed the research literature on the epidemiologic relationship between blood pressure levels and calcium, with an emphasis on dietary intake. A conceptual framework for causal inference is summarized; then the designs and results of observational and intervention studies are presented. Of 25 reports of observational studies relating intake of calcium or calcium-rich foods to blood pressure, the majority found some evidence of an inverse association. However, many analyses did not support this relationship, and only two studies have confirmed the inverse association with a prospective design. Nineteen randomized controlled clinical trials of calcium supplementation have been reported, excluding those exclusively in pregnant women. Eleven of these showed no significant effects on
dose-response relationship; time order (effect follows cause); response to experimental manipulation; and plausible biologic mechanism. These criteria require some elaboration, particularly as they apply to the calcium blood pressure hypothesis.
Specificity and Confounding Variables that are associated both with the cause and the effect must be controlled either in the design or the analysis, to be certain that the primary association is specific. The traditional techniques are matching and stratification (subgrouping). However, for more than a few covariates—usually the situation with BP studies—multiple adjustment techniques using statistical models are more powerful. Use of these models with nutrient data focuses attention on the problem of multicolinearity, ie, the high intercorrelations of intakes of certain nutrients. Another pitfall of complex multivariate models is overadjustment, by which is meant removing an apparent effect of a factor by including in the model an intervening variable related to the mechanism; a possible example is including both dietary and serum calcium. 5
Consistency of Associations This refers simply to whether an association is found repeatedly in different studies of similar populations, and to some extent, in diverse populations. The latter can be examined among strata of a single study as well. However, distinguishing between real and chance differences in the association among study populations and subgroups is difficult, and is facilitated by clear prior hypotheses about such variability. Dose-Response Gradations of effect depending in a regular manner upon levels of the exposure to the tested compound, in this case dietary calcium, strengthens a causal inference. A useful approach is classifying intake into quantiles (eg, deciles), and examining mean BP across these strata. Time Order Most of the observational epidemiologic studies of calcium and BP have been crosssectional, a design which cannot establish whether diet has determined current BP levels, or, for example, diet changes
Intervention Studies Properly conducted clinical trials can overcome many of the problems in interpreting nonexperimental epidemiologic data, including time order and various other sources of confounding. Indeed, clinical trials provide the strongest type of evidence both for causality and for the ability to affect the disease or condition to the benefit of patients or healthy individuals. Among the limitations of trials, however, is the uncertainty about the necessary length of follow-up to allow sufficient time for a biologic effect. Most trials of calcium supplementation have lasted a few weeks or months. Also, trials should have one or more primary hypotheses stated a priori, including the outcome variable, as well as which data points of the multiple measurements of the variable will be used and how the data will be analyzed, to ensure proper and unbiased use of significance testing at the conclusion. Biologic Mechanisms Knowledge of physiologic, cellular and molecular mechanisms gained from human and animal experimentation can lend much weight to epidemiologic conclusions, but a complete theory of the chain of events is not required for useful application of epidemiologic evidence. OBSERVATIONAL STUDIES ON DIETARY CALCIUM We have reviewed 25 reports of studies conducted in 17 populations, not including subsets (Table l ) . Ten of the populations are from US states and territories, 6 from Western Europe, and 1 from South Africa. There are 2 reports from the Western Electric Study (Chicago), 4 papers from the Honolulu Heart Program (Japanese men living in Hawaii), and 6 from the US National Health and Nutrition Examination Surveys (NHANESI and II). Most subjects have been adults; most studies included both sexes, and some included blacks. Regarding design, all but 1 have been basically crosssectional; three had a longitudinal component as well, but 1 of them did not include milk intake as a variable, since it did not have an independent effect crosssectionally. The sample sizes ranged from 100 in a few studies to around 58,000 in the Nurses' Health Study. In their designs or analyses most studies controlled for effects of age, race, sex and body weight. Otherwise, adjustment for other potential confounders was highly variable, as indicated in Table 1. A particular methodologic issue in these studies is the method of dietary data collection. Any method is subject to recall and reporting errors, and sbme bias is likely if the specific purpose of the study is known to subjects and/or research staff. However, an intent to evaluate the role of calcium intake appears to not have been obvious in most of the studies. Most of the studies 5 - 2 8
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Measures of Association Most commonly cited are the relative risk (or odds ratios) for a disease (ie, hypertension) or the regression/correlation coefficient, for a continuous variable (ie, BP), the latter usually being the more sensitive measure. Either (including standardized coefficients) can be used for statistical significance testing and expression of the result, but for interpreting the medical significance, unstandardized coefficients or relative risks are needed, and are cited in this review whenever available. Relative risks of 1.5 or greater are often considered important effect sizes for knowledge and action.
have been made in response to knowledge of BP levels. More longitudinal studies are needed.
TABLE 1. OBSERVATIONAL STUDIES OF DIETARY CALCIUM AND BLOOD PRESSURE: DESIGN FEATURES
Langford 1973 McCarron 1982
Mississippi blacks Oregon
6
7
Ackley 1983 Garcia-Palmieri 1984 Connor 1984 Nichaman 1984 Zhang 1988
California whites Puerto Rico Oregon Chicago whites Same as above
8
9
10
11
12
Hawaii, Japanese-Americans Same as above Same as above US black/white from NHANES I
13
5
14
15
Harlan 1984A Harlan 1984B Gruchow 1985 Harlan 1985 Sempos 1986 Kromhout 1985 Sowers 1985 Kok 1986 Steyn 1986
16
17
18
same, NHANES I same, NHANES II same, NHANES I/II Zutphen Iowa Amsterdam South Africa, "col ored" Wales Denmark Italy US nurses
19
21
20
22
23
25
24
Elliott 1987 Thomson 1987 Trevisan 1988 Witteman 1989
Study design
School girls 35 M, mean = 42 55 F, mean = 39 MF, 3 0 - 7 9 M, 4 5 - 6 4 MF, 16-65 M, 4 0 - 5 5 Same as above
X-sect case-control
55 46u44 5,050/541 Mf 7,932 407 1,976/1,014 1,884/1,450
M, 4 5 - 6 4 Same as above Same as above Same as above MF, 18-74
X-sect X-sect X-sect X-sect/prosp Same as above X-sect/prosp X-sect X-sect X-sect X-sect
MF, 2 5 - 7 4 MF, 2 5 - 7 4 MF, 18-74 MF, 2 1 - 7 4 MF, 4 0 - 7 4 M, 4 0 - 5 9 F, 2 0 - 3 5 , 5 5 - 8 0 MF, 4 0 - 6 5 MF, 15-64
X-sect X-sect X-sect X-sect X-sect X-sect/prosp X-sect X-sect X-sect
J HR,SES, 2,055 I [serum Ca,P, AAT,+ 5,468 J 9,555 Not sex 5,305 Alcblood Pb,+ 5,840/5,490 794/605/498}: Cal,alc,K 86/222 Ale 2,291 cal,alc,HR,+ 976 Race only
26
27
M, 4 5 - 4 9 F, mean = 50 MF, 2 0 - 5 9 F, 30-55
X-sect X-sect X-sect Prosp
356 103 4,354 58,218
28
29
Sample size
8,006/6,858 6,496 615 7,011 10,732
Covariates controlled* Not body weight Body weight "com parable" Alct Alc,Hr,educ,+ Alc,SES,fatty acids Ale Alc,HR,FH,+ Alc,PA,K Alc,K Body weight
Ale Alc,fatty foods Alc,K,Mg,fiber
* In addition to age, sex, race, and body weight, j Subset, χ Number at successive exams. Abbreviations: ATT = aspartate amino-transferase, Ale = alcohol, Ca = calcium, Cal = calories, educ = education, F — females, PH = family his tory, HR = heart rate, Κ = potassium, Μ = males, NHANES = National Health and Nutrition Examination Survey, Ρ = phosphorous, PA = physical activity, Pb = lead, prosp = prospective, SES = socioeconomic status, WT = weight, X-sect = cross-sectional, + = additional covariates.
have used the 24 h recall as their main instru ment 5,7-10,13,14,16-21,23,24 t h o d has satisfactory precision for groups of people, but in correlation/regression analyses, in which individuals are the units of analysis, random day-to-day variation tends to produce false negative results. Five of the studies relied on a variety of food-frequency questionnaires, aimed at usual intake. ' ' ' Some examples of this kind of questionnaire have been shown to provide estimates of calcium intake that correlate well with more laborious diet histories. The Western Electric study ' used an in-depth "reference standard" method for obtaining a four week diet history, and the Caerphilly Heart Study used a seven day weighted dietary record. The first report of a calcium-blood pressure associa tion was apparently Langford's description of a low cal cium intake, and a low urinary ratio of sodium to cal cium, in black schoolgirls with high systolic BP (SBP) levels. No details of this study have been published. Next, McCarron's case-control study, comparing agem e
15
30
22
25,27
28
11 12
26
6
sex-race matched hypertensives and normotensive vol unteers, found a significantly lower intake of calcium from food in the former, mostly of nonmilk dairy prod ucts. There were no differences in intake of calories, sodium, or potassium, nor (it was stated) in body weight. A crude relative odds for hypertension ( < 1 g calcium ν > 1 g) can be calculated as 3.2, but it should be em phasized that this is without adjustment for other risk factors, including alcohol intake. In the Rancho Bernardo cohort, Ackley found an in verse relationship with milk intake in men, significant for diastolic but not systolic BP, but no such relationship in women. In a subset of 541 men with 24 h recall data, diastolic BP (DBP) was also associated inversely with total food calcium, while SBP was associated inversely with milk calcium; these analyses were controlled for alcohol intake. Another report of mostly positive results for men came from the Puerto Rico Heart Study, which described numerous analyses, all stratified by age and urban-rural residence and adjusted for a number of im7
8
9
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Reed 1982 Reed 1985 Joffres 1987 Criqui 1989 McCarron 1984
Gender, age (years)
Region, race (if given)
Author, year
10
11
11
12
13
5
14
for magnesium and for potassium. In each case the highest quartile was lower by about 5 to 6 mm Hg systolic, and 2 to 3 mm Hg diastolic, than the lowest quartile. Most recently, Criqui evaluated the separate and combined effects of calcium, potassium and alcohol intake. Calcium was inversely related to systolic and diastolic BP only in nondrinkers and light drinkers. The absence of an association among moderate to heavy drinkers led the authors to suggest that malabsorption of calcium might explain a small part of the large hypertensive effect of alcohol. Two large data sets on this topic come from the two National Health and Nutrition Examination Surveys (NHANES). There have been five reports on calcium and BP from NHANES I (1971 to 1974) on different but overlapping subsets of the s a m p l e , and two from NHANES II (1976 to 1 9 8 0 ) . ' Subject-related exclusion differed somewhat, but most of the differences were based on availability of biochemical measures on subsamples. For the most part, analyses were based on a single 24 h recall. Categorical analyses used various definitions of hypertension as the response variable. In NHANES I, McCarron found a significant inverse association with systolic hypertension, but various aspects of the analysis, including adequacy of adjustment for body mass, have been questioned. ' In NHANES II, Harlan found inverse associations of both diastolic hypertension and isolated systolic hypertension with frequency of calcium-rich foods in three of four age-sex strata, but without control for any covariates. Analyses using continuous BP are probably more informative, and findings have been inconsistent. In NHANES I, McCarron reported a correlation coefficient between calcium intake and SBP of — 0.6, uncontrolled for any confounders. Harlan, stratifying by sex and race (four groups), found four significant associations between calcium intake and SBP or DBP among the eight examined, two direct and two inverse; the latter were in blacks and women. He adjusted for many potential confounders; in fact, including serum calcium could be considered overadjustment. In a later report without race stratification, an inverse association was found only for SBP in older women. Gruchow reported no overall association with SBP in his unstratified analysis, adjusting for age, race, and body mass. In probably the most straightforward analyses, Sempos examined mean BPs by quintile of calcium intake for four sex-race strata, excluding subjects under age 40, and found significant inverse association only for black men, with strong similar trends for black women. He described similar results for NHANES II especially in black women, but none of the associations was significant, perhaps because the number of blacks was substantially less. Sempos's analyses were adjusted for age and body mass, but not for alcohol intake. Harlan's findings for NHANES II are not directly comparable, because they were not race-stratified, but are consistent in that an 15
16-20
20
21
16
30 31
21
16
17
18
19
20
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portant covariates (Table 1). The associations were mainly between SBP and milk or milk calcium intake, and were significant in each stratum except young rural men. The size of the effect was about 0.5 mm Hg per 4 oz milk. In the urban strata a dose-response relationship was apparent, with a relative risk for hypertension of about two, comparing no milk intake with 32 oz/day. Conner sampled families and reported diet-blood pressure relationships separately for male and female spouses. In this small study correlation coefficients were mostly positive (ie, greater calcium intake, higher BP levels), but only for SBP in men was this significant. Alcohol intake was not controlled in the analysis. The first report of a prospective analysis came as an abstract from the Western Electric study, later extended in another abstract (Ref. 12, and personal communication). As in most of the previous studies, an inverse relationship was found crosssectionally in these white men, for both SBP and DBP, with adjustment for the main covariates. However, results of the prospective analyses were inconsistent: Nichaman found no association between baseline calcium and eight year incidence of one or more measurements of DBP ^ 9 5 mm Hg, while Zhang reported an inverse relationship for onset of relatively severe DBP elevations, but not for less extreme levels, and no association with incidence of systolic hypertension, during seven years of follow-up. The four reports from the Honolulu Heart Program represented important further explorations of a calcium-blood pressure relationship. Reed's first paper presented analyses excluding only men on antihypertensive drugs and found significant inverse associations at the baseline exam between milk intake and both SBP and DBP, adjusting for age and body mass. However, the associations were lost when 8 to 11 other variables, including alcohol, heart rate, and family history of hypertension, were added in multiple regression analyses. Therefore, milk intake was not included in the six year prospective analysis of BP change. In the next paper men on a special diet, and those with cardiovascular disease, were excluded, and calcium from food, primarily dairy, was highly associated with SBP and DBP, even controlling for alcohol and physical activity. The contrast between the two analyses could be explained if family history, milk (dairy calcium) intake, and sympathetic activity (heart rate) were all involved in a single causal chain. In the second analysis, potassium and calcium intake were found to be highly correlated, and with both in the regression, calcium was no longer related to BP. Reed pointed to this as an example of the problem of multicolinearity, and the need for intervention trials for resolution. Subsequently, Joffres reported findings from a subset reexamined during 1970 to 1972, which reinforced the point about specificity in a different way: the significant associations (age- and body mass-adjusted) between BP and food calcium were very similar in magnitude and direction to those
21
22
23
24
25
26
27
28
29
It would be very difficult to summarize these studies quantitatively, because of variations in methodology. Although a simple count of studies or strata within stud ies indicates somewhat more positive than negative results regarding an inverse association, there is consid erable inconsistency. There are several possible explana tions. A few analyses have not controlled adequately for
powerful confounding variables, such as obesity and alcohol intake; both these factors would probably tend to produce spurious associations between low calcium intake and higher BP in crosssectional studies. On the other hand, as Sempos has pointed out, large day-to day variability of calcium intake for individuals, com pared to variation among individuals, would tend to lead to false negative results. Also, several of the nega tive studies have had the smallest sample s i z e s . ' ' When results are inconsistent, true heterogeneity of effect among subgroups is a possibility, but except per haps for blacks in NHANES, there is little indication of demographic variation (age, sex, etc). A more biologi cally grounded hypothesis would be a nonlinear rela tionship, such that an effect is more apparent when calcium intake is low. However, that does not seem to explain many of the differences among populations, eg, an effect was found in Puerto Rican men, who had relatively high intake (about 1 g), while an effect was more apparent in black men in NHANES I than in white women, even though the latter had lower estimated intake (601 ν 722 mg/day). Other possible effect modifi ers that have been suggested include vitamin D, men tioned above, and dietary sodium intake. 20
10
23
23
26,27
32
RANDOMIZED TRIALS OF CALCIUM SUPPLEMENTATION As stated above, randomized clinical trials testing the effect of oral calcium salts on BP change provide data that overcome many of the problems of observational studies. Table 2 summarizes design features and the results of 19 trials reported between 1983 and 1989 27,33-50 (Using a variety of search techniques, in cluding a computerized literature search, we have iden tified no additional randomized trials through October 1989). As there is another paper in this symposium that discusses the intervention studies in detail, this review is brief. Several trials conducted during pregnancy are ex cluded. Nine of the trials studied nonhypertensive sub jects, exclusively in seven of t h e s e . ' The groups ranged from young adults, to postmenopausal wo men. Three included both sexes, three studied men only, and three women only. Most of the trials were double-blind. (Only the test of calcium-enriched yeast was blind in Vinson's study. ) Six had parallel group designs, with sample sizes ranging from 14 to 8127,33,35,37-39; fa three with crossover designs had 7, 32, and 50 subjects each. ' ' Intervention and followup lasted from six weeks to four years, with a median of eight weeks. The dose of elemental calcium was 0.5 to 2 g; seven trials used 1.0 to 1.5 g. The calcium was ad ministered as tablets containing either a single calcium salt, or a combination of two compounds, except for one dietary trial and the yeast arm of Vinson's trial. For primary results of each trial we used changes through end of follow-up in seated (or if not given, 27
33-40
33
27
39
e
34
37
36
40
39
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inverse association was found for all women combined, with adjustment for alcohol intake, blood lead, and other covariates. Eight other studies, including five from Western Eu rope, have been published in the past five years, with mixed results. Using a diet history to estimate calcium from food over a 6 to 12 month period, Kromhout found significant inverse relationships with SBP and DBP in the Zutphen cohort at the 1965 and 1970 exams, but not at the 1960 exam. Potassium intake was in cluded in the analyses. However, changes in calcium intake were not related to changes in BP in these men over either five year period. Sowers included calcium from diet supplements and drinking water in her esti mates of intake, and found only weak nonsignificant inverse associations with SBP, in both younger and older women. A subgroup analysis did suggest in creased SBP in those with both low calcium and low vitamin D. Steyn reported univariate inverse associa tions of hypertension with intakes of calcium, as well as potassium, magnesium, and saturated fat, but no data were presented. Kok used a food frequency question naire to estimate calcium over a one week period, and found significant inverse relationships except with DBP in men, adjusting for most confounders but not other micronutrients. Elliott based estimates of dietary in take on carefully recorded seven day food records, but found no associations of BP or hypertension with any nutrients except protein intake, in middle-aged men not on antihypertensive medication. Thomsen divided a small sample of postmenopausal women by tertiles of calcium intake, and found no differences in SBP or DBP among them. Trevisan related frequency of consum ing various calcium-rich foods to BP levels, and found significant inverse associations mainly between whole milk and systolic BP. Coefficients had the opposite (posi tive) sign for skim milk, perhaps because those with higher BP were attempting to reduce cardiovascular risk by lowering dietary fat. Finally, the only purely prospec tive study of dietary factors, including calcium, in rela tion to BP was the Nurses's Health Study, reported in 1989. It supported the results of many of the crosssectional studies by showing that over a four year period the relative risk of self-reported hypertension for a cal cium intake greater than or equal to the current Recom mended Daily Allowance, 800 mg/day, was 0.78 (sta tistically significant in this large cohort) when compared with an intake of less than 400 mg/day. These analyses were controlled for intake of alcohol, magnesium, potas sium and fiber.
TABLE 2. RANDOMIZED TRIALS OF CALCIUM SUPPLEMENTATION
Belizan 1 9 8 3
Dose (g)
SBP (P)**
DBP (P)
18-35 MF ?age Μ 35-65 F 35-65 F 21-70 MF, W(B) 21-70 MF, W(B) 21-75 MF, BW 16-29 M(F) 43 mean MF 18-75 F(M), B(W) 43 mean M(F) 58 mean M(F) 20-23 F 49 mean MF, BW 48 mean MF 19-52 M, W(B)
Parallel DB, plac X-over plac Parallel DB, plac Parallel DB, plac X-over DB, plac X-over DB, plac X-over DB, plac Parallel DB, plac X-over DB, plac Parallel DB, plac X-over DB, plac Parallel DB, plac Parallel DB, plac X-over DB, plac X-over DB, plac Parallel DB, plac
57
22 wks
1.0
7
6 wks
1.0
F:-2(.01) M: —1(.35) + 5(NS)
-4(.0001) -6(.0001) + 2(NS)
Sunderrajan 1 9 8 4
81
4 yrs
1.5
+ 2(NS)
+ 2(NS)
34
4 yrs
1.5
-20(.06)
-l(NS)
32
8 wks
1.0
-2(NS)
-3(.05)
48
8 wks
1.0
-4(.02)
0(NS)
17
8 wks
0.8
90
12 wks
1.0
17
15 wks
1.0
32
4 wks
1.5
21
8 wks
1.0
+ 4(NS)
+ 2(NS)
47
2 mos
58
6 wks
0.4 0.8 1.5
-4(NS) + 1(NS) -1.7(NS)
+ 1(NS) 0(NS) + 0.4(NS)
18
4 wks
0.4
+ 4(NS)
+ 1(NS)
18
5 days
1.0
-5(.05)
0(NS)
75
12 wks
1.5
Ν
postmenopausal
28
lyr
2.0
Ν
19-24 Μ
14
7 wks
0.5 (glucose) 0.5(yeast)
+ 7.0(7) + 7.4(NS)
0(NS) -5.3(.01)
Ν
21-65 MF 41 mean M(F) 39-67 M(F)
Parallel DB, plac Parallel BP/open (see text) X-over open X-over
50
8 wks
1.15 (diet)
-2(.02)
-l(NS)
14
4 wks
1.0
+ 2(NS)
+ 0.7(NS)
27
1 wk
2.16
-10.4
-2.3
Ν
34
Ν
35
Η McCarron 1 9 8 5
Ν
36
Η Meese 1 9 8 6
Η
41
Grobbee 1 9 8 6
Η
42
Strazzullo 1 9 8 6
Bloomfield 1 9 8 6 Zoccali 1 9 8 6
Η
43
Η
44
Η
45
Nowson 1 9 8 6
Η
46
Van Beresteyn 1 9 8 6
37
Ν
Capuccio 1 9 8 7
47
Η
Lasaridas 1 9 8 7
48
Η
Lyle 1 9 8 7
Ν
38
Thomsen 1 9 8 7 Vinson 19 8 7
27
39
Bierenbaum 1 9 8 8
40
Siani 1 9 8 8
49
Η
Saito 1 9 8 9
50
Η
Parallel DB, plac
No effect -2(.ll)
-0(NS) -2(NS)
-l(NS)
No effect
W:-4 -1 B:-7 -1 (P = .01, races combined) -4(NS) 0(NS)
(P = .01 for mean BP) * A negative sign indicates treatment group reduced more than control group. ** The Ρ value reflects the main analysis done by the authors. Abbreviations: Β = blacks, BP = blood pressure, DB = double-blind, F = females, Η = hypertensive, Μ = males, Ν = normotensive, NS = nonsignificant, plac = placebo, W = whites, X-over = crossover.
supine) SBP and DBP. Of the nine trials, t w o had positive results, ie, SBP and DBP were significantly re duced (except SBP in males in Belizan ); four had nega tive results ' ' ' (a nonsignificant rise in BP in two studies); and three had mixed results. Among the latter an effect was seen for SBP or DBP, but not both, in t w o ' ; in the third an effect on SBP only was seen for calcium yeast, but not for calcium gluconate. In order to provide a more powerful test of the hy pothesis and a more quantitative summary of these 3338
33
27 34 35 37
36
40
39
trials, we have pooled the observed BP changes, weighting each trial, or stratum within the trial, by the inverse variance of the treatment effect, ie, for both SBP and DBP, the mean change in the treatment group minus mean change in the control group (see Appen dix). The resulting pooled estimates and 9 5 % confi dence limits were as follows: SBP, —1.3 mm Hg (—3.2, + 0.8), and DBP - 1 . 3 ( - 2 . 6 , - 0 . 1 ) . Thus, only the dia stolic effect was marginally significant, ie, a two-sided P
