close

Вход

Забыли?

вход по аккаунту

?

125

код для вставкиСкачать
2003
Calcium Channel Blockers, Cancer Incidence, and
Cancer Mortality in a Cohort of U.S. Women
The Nurses’ Health Study
Karin B. Michels, Sc.D.1,2
Bernard A. Rosner, Ph.D.1,3
Alexander M. Walker, M.D.2
Meir J. Stampfer, M.D.1,2,4
JoAnn E. Manson, M.D.1,2,5
Graham A. Colditz, M.D.1,2
Charles H. Hennekens, M.D.2,5
Walter C. Willett, M.D.1,2,4
1
Channing Laboratory, Department of Medicine,
Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts.
2
Department of Epidemiology, Harvard School of
Public Health, Boston, Massachusetts.
3
Department of Biostatistics, Harvard School of
Public Health, Boston, Massachusetts.
4
Department of Nutrition, Harvard School of Public
Health, Boston, Massachusetts.
5
Division of Preventive Medicine, Department of
Medicine, Harvard Medical School and Brigham
and Women’s Hospital, Boston, Massachusetts.
Supported by research grant CA 40356 from the
National Cancer Institute, National Institutes of
Health, Bethesda, Maryland.
The authors thank Professor Frank E. Speizer,
M.D., principal investigator of the Nurses’ Health
Study, for helpful advice regarding the analysis
conducted in this study and regarding the manuscript. They also thank the participants in the
Nurses’ Health Study for providing the relevant
information necessary for this analysis.
Address for reprints: Karin B. Michels, Sc.D.,
Channing Laboratory, 181 Longwood Avenue, Boston, MA 02146.
Received January 26, 1998; accepted April 6,
1998.
© 1998 American Cancer Society
BACKGROUND. Some studies have suggested that the use of calcium channel
blockers may increase the risk of cancer. A possible association of the use of
calcium channel blockers with cancer incidence and cancer mortality was addressed using data from the Nurses’ Health Study.
METHODS. In this study, a total of 18,635 female nurses reported regularly taking at
least 1 of 4 cardiovascular medications in 1988: diuretics, beta-blockers, calcium
channel blockers, and/or angiotensin-converting enzyme (ACE) inhibitors. Cancer
incidence and cancer deaths were ascertained until 1994.
RESULTS. During 6 years of follow-up, 852 women were newly diagnosed with
cancer and 335 women died of cancer. Women who reported the use of calcium
channel blockers had no increased risk of newly diagnosed cancer compared with
those taking other cardiovascular drugs (relative risk ⫽ 1.02; 95% CI 0.83–1.26). The
relative risk of dying from cancer associated with the self-reported use of calcium
channel blockers was 1.25 (95% CI 0.91–1.72). Relative risks were adjusted for the
following self-reported factors: age; weight; height; cholesterol level; systolic and
diastolic blood pressure; smoking; alcohol intake; physical activity; menopausal
status; postmenopausal hormone use; aspirin use; and history of diabetes, cancer,
stroke, myocardial infarction, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, angina, and hypertension. Regarding site specific
cancer incidence and mortality, only lung cancer incidence was somewhat increased (RR ⫽ 1.61; 95% CI 0.88 –2.96).
CONCLUSIONS. These data suggest no important increase in overall cancer incidence or cancer mortality related to the self-reported use of calcium channel
blockers. Cancer 1998;83:2003–7. © 1998 American Cancer Society.
KEYWORDS: epidemiology, cancer incidence, cancer mortality, calcium channel
blockers, apoptosis.
C
alcium channel blockers have recently been associated with a
possible increase in the incidence of cancer. An increased risk of
cancer was first reported by Pahor et al.1,2 Among 750 hypertensives
who were cancer free at baseline, the relative risk (RR) of developing
cancer was found to be 2.02 (95% CI 1.16 –3.54) for those taking
calcium channel blockers (27 events) as compared with those taking
beta-blockers (28 events).1 In the full cohort (not restricted to hypertensives), relative risks for cancer were 1.72 (95% CI 1.27–2.34) for
reported use of calcium antagonists compared with those not taking
them; the highest risk was associated with verapamil (RR ⫽ 2.49; 95%
CI 1.54 – 4.01).2
In a small Swedish case– control study, patients with colon carcinoma had taken verapamil more often than control participants,
2004
CANCER November 1, 1998 / Volume 83 / Number 9
but only 11 participants (10 cases, 1 control) reported
the use of verapamil.3 In a British case– control study,
Jick et al. reported an odds ratio for cancer of 1.27
(95% CI 0.98 –1.63) for users of calcium channel blockers (178 cases) compared with users of beta-blockers
(183 cases).4 In a cohort in Germany, no increase in
cancer incidence was observed with calcium channel
blockers.5 An elevated risk of breast carcinoma was
recently attributed to the use of calcium channel
blockers based on a multisite cohort study.6 Fitzpatrick et al. reported a hazard ratio of 2.57 (95% CI
1.47– 4.49) for women who used calcium channel
blockers (20 cases) compared with women who did
not use them (55 cases).6 Most recently, a large casecontrol study including 9513 incident cancer cases
yielded a relative risk of 1.1 (95% CI 0.9 –1.3) for the
use of calcium channel blockers.6a
It has been suggested that calcium channel blockers increase the risk of cancer by inhibiting apoptosis,7
the programmed cell death by DNA fragmentation of
dysfunctional and old cells.8 Intracellular calcium ion
balance regulates apoptosis in vitro9,10 and calcium
antagonists inhibit apoptosis in vitro.11,12 Animal data
are not available.
In the Nurses’ Health Study, we investigated
whether self-reported use of calcium channel blockers, beta-blockers, or angiotensin-converting enzyme
(ACE) inhibitors, relative to the use of diuretics, was
associated with incidence of or mortality from cancer.
METHODS
Study Population and Data Collection
The Nurses’ Health Study was initiated in 1976 and
includes 121,701 female registered U.S. nurses who
were ages 30 –55 years at the time of entry. Participants are followed through biennial self-administered
questionnaires. On baseline and follow-up questionnaires, nurses are asked to provide demographic and
life-style information as well as their disease status.
In 1988, information was requested on the regular
use of cardiovascular medications, including thiazide
diuretics, beta-blockers, calcium channel blockers,
and ACE inhibitors. Participants were asked, “Are you
currently taking any of the following medications at
least once a week?” On the questionnaire, medications
were identified only as classes of pharmaceutical
drugs (with examples), as listed above. Information on
the use of calcium channel blockers was not updated
until 1994; therefore, medication use was not updated
in the analysis. According to self-reported information
on medications from 1994, 57% of women who reported calcium channel blocker use in 1988 were still
using them in 1994. Of women who used other or no
medications in 1988, 14% reported use of calcium
channel blockers in 1994. In 1988, long-acting calcium
channel blockers were rarely prescribed; it can therefore be assumed that the majority of calcium antagonists were short-acting formulations.
The endpoints included in this analysis were cancer incidence and cancer mortality. Cancer mortality
analyses included women with prevalent cancers in
1988. All women who reported cancer were contacted
for permission to review the relevant hospital records
and confirm the self-reported diagnosis. Study physicians blinded to the exposure information reviewed
the medical records to extract information on the histologic type, the anatomic location, and the stage of
the cancer.
Deaths of study participants have been ascertained since the beginning of the Nurses’ Health Study
in 1976. The mortality surveillance includes the National Death Index to identify any deaths among participants who did not respond during each questionnaire cycle. This surveillance supplements reports by
the subjects’ next of kin and by postal authorities.
Mortality follow-up has been estimated to be 98%
complete for this cohort.13 When deaths were identified, written permission was requested from the next
of kin to review the medical records and obtain pathology reports.
Statistical Analysis
Analyses were restricted to women who reported in
1988 that they took thiazide diuretics, beta-blockers,
calcium channel blockers, ACE inhibitors, or any combination. Women who reported use of both calcium
channel blockers and ACE inhibitors were excluded
due to inadequate sample size (n ⫽ 209). Women were
also excluded from the analysis if their year of birth
(n ⫽ 5), smoking status in 1988 (n ⫽ 40), menopausal
status in 1988 (n ⫽ 48), or weight or height (n ⫽ 29)
was unknown, or if their date of death was prior to
1988 or not yet known (n ⫽ 110); these exclusions left
a study population of 18,635 women. During the
6-year observation period, 684 women (3.7%) died and
502 (2.7%) were lost to follow-up.
Person-time of follow-up was allocated to each
participant starting with the return of the 1988 questionnaire and accumulated up to May 1, 1994, or the
diagnosis of cancer or death, whichever occurred first.
A total of 107,256 person-years were accumulated.
Drug exposure was classified according to the 1988
responses throughout the follow-up period, without
further updating. Cancer incidence or mortality rates
were calculated for each pharmaceutical agent by dividing the number of events by the person-time of
follow-up for that agent. Relative risks were estimated
as ratios of incidence rates, comparing women who
Calcium Channel Blockers and Cancer/Michels et al.
reported regular use of calcium channel blockers with
women who used other cardiovascular drugs. To control simultaneously for other potential risk factors, a
pooled logistic regression model was used, in which
risk sets were updated every 2 years.14 In estimating
the cause specific hazard for cancer death, we censored deaths from other causes at each 2-year interval,
thus conditioning on survival up to that age.15 We
calculated 95% confidence intervals around the relative risks.16
Age-adjusted relative risks were obtained for all
medications considered and for any combinations
used. Covariate-adjusted relative risks were calculated, with adjustment for various self-reported risk
factors: age; weight; height; cholesterol level; systolic
and diastolic blood pressure; smoking; amount of current smoking; alcohol intake; regular physical activity,
defined as working up a sweat at least once a week;
menopausal status; current postmenopausal hormone
(PMH) use for at least 5 years; use of aspirin on at least
5 days each month; and history of diabetes, cancer,
stroke, myocardial infarction, coronary artery bypass
graft (CABG) or percutaneous transluminal coronary
angioplasty (PTCA), angina pectoris, or hypertension
in or prior to 1988.
RESULTS
The distribution of risk factors and history of disease
among women who reported use of calcium channel
blockers and those who reported other medications is
displayed in Table 1. Women prescribed calcium
channel blockers were more likely to have a history of
diabetes, pulmonary disease (asthma, chronic bronchitis, or emphysema), or ischemic heart disease
(myocardial infarction, angina pectoris, or CABG/
PTCA). Women who reported use of other medications were more likely to be hypertensive.
Of the 18,635 nurses included in this analysis, 852
were newly diagnosed with cancer between 1988 and
1994, and 335 died of cancer during this follow-up
period. Total cancer incidence was not found to be
associated with the use of calcium channel blockers
(Table 2). No association was found between calcium
channel blocker use and breast carcinoma incidence.
Of the site specific cancers, only lung carcinoma incidence was elevated among women who reported calcium channel blocker use (RR ⫽ 1.96; 95% 1.15–3.33;
adjusted for age, smoking status in 1988, and mean
number of cigarettes smoked per day among women
who smoked in 1988). When additional adjustment
was made for age at the start of smoking, multiple
drug use, weight, height, alcohol intake, physical activity, menopausal status, and postmenopausal hormone use, the relative risk was slightly higher. After
2005
TABLE 1
Risk Factor Profile and Concomitant Disease among Regular
Users of CCB, Compared with Users of Cardiovascular
Medications (thiazide diuretics, beta blockers, ACE inhibitors) Other
than CCB, Self-Reported in 1988 among 18,635 Participants in the
Nurses’ Health Study
Risk factors/Concomitant Disease
CCB
No CCB
Total no. of participants
Mean age (yrs)
Mean weight (kg)
Mean heighta (cm)
Mean cholesterolb (mg/dL)
Mean systolic BPb (mmHg)
Mean diastolic BPb (mmHg)
Current smoker (%)
Former smoker (%)
Amount smokedb,c
Alcohol intaked (gm/day)
Regular physical activitye
Postmenopausal
Current PMH use for 5⫹ yrs
Aspirin intakef
Diabetes
Pulmonary disease
Cancer
Myocardial infarctiong
Angina pectorisg
CABG/PTCAg
Strokeg
Hypertensiong
2361
58.0
71.9
163.3
220.5
135.8
84.2
396 (16.8)
1009 (42.7)
19.4
5.6
899 (38.1)
2131 (90.3)
340 (14.4)
1008 (42.7)
321 (13.6)
382 (16.2)
200 (8.5)
362 (15.3)
605 (25.6)
105 (4.5)
65 (2.8)
918 (38.9)
16,274
56.8
73.2
163.8
212.9
136.1
85.1
2686 (16.5)
6391 (39.3)
18.5
6.3
6391 (39.3)
13,787 (84.7)
2455 (15.1)
5834 (35.9)
1386 (8.5)
1721 (10.6)
1453 (8.9)
518 (3.2)
1003 (6.2)
112 (0.7)
229 (1.4)
11,482 (70.6)
CCB: calcium channel blockers; ACE: angiotension-converting enzyme; PMH: postmenopausal hormone; CABG/PTCA: coronary artery bypass graft or percutaneous transluminal coronary angioplasty.
a
Data for 1976 is given.
b
Average values were calculated as mean values from prespecified categoric responses.
c
Mean no. of cigarettes smoked per day among current smokers in 1988.
d
In grams per day; includes women who do not drink alcohol.
e
Assessed in 1980; regular physical activity was defined as working up a sweat at least once a week.
f
Regular aspirin intake was defined as use on at least 5 days each month.
g
Categories are mutually exclusive with the following hierarchy: 1) stroke, 2) myocardial infarction, 3)
CABG/PTCA, 4) angina pectoris, 5) hypertension.
additional adjustment for cardiovascular risk factors
as well as concomitant cardiovascular disease and
diabetes, the relative risk was somewhat attenuated
(RR ⫽ 1.78; 95% CI 0.98 –3.23) (Table 2). When pulmonary disease in or prior to 1988 and years since women
stopped smoking were also controlled in the analysis,
the relative risk for lung carcinoma was 1.61 (95% CI
0.88 –2.96). For women who had ever smoked, the
covariate-adjusted relative risk was 1.55 (95% CI 0.80 –
3.02), additionally adjusted for a history of pulmonary
disease and years since women stopped smoking. Calcium channel blocker users had a relative risk of
smoking-related cancers (lung, pancreatic, kidney, or
bladder carcinoma) of 1.68 (95% CI 1.06 –2.65, adjusted for all covariates, including prior pulmonary
disease and years since women stopped smoking).
2006
CANCER November 1, 1998 / Volume 83 / Number 9
TABLE 2
Relative Risk (95% Confidence Interval) of Site Specific Cancer Incidence and Mortality between 1988 and 1994, According to Use of CCB SelfReported in 1988 among Women in the Nurses’ Health Study
CCB
Cancer site
Total cancer
Incidence (n ⫽ 16,954)
Mortality
Breast carcinoma
Incidence (n ⫽ 16,482)
Mortality
Lung carcinoma
Incidence (n ⫽ 16,746)
Mortality
Colon carcinoma
Incidence (n ⫽ 16,981)
Mortality
Cancer of the lymphatic system
Incidence (n ⫽ 16,978)
Mortality
No CCB
Covariate-adjusted
relative risk I
(95% CI)a
CCB vs. no CCB
Covariate-adjusted
relative risk II
(95% CI)b
CCB vs. no CCB
Events
Person-years
Events
Personyears
Age-adjusted relative
risk (95% CI)
CCB vs. no CCB
122
54
12,206
13,404
730
281
84,787
93,852
1.09 (0.90–1.33)
1.23 (0.92–1.65)
1.10 (0.90–1.34)
1.27 (0.94–1.71)
1.02 (0.83–1.26)
1.25 (0.91–1.72)
51
13
11,807
13,404
304
77
82,524
93,852
1.12 (0.83–1.51)
1.12 (0.62–2.02)
1.16 (0.86–1.57)c
1.13 (0.61–2.07)
1.07 (0.78–1.48)c
1.33 (0.70–2.54)
18
14
12,170
13,404
56
56
84,588
93,852
1.96 (1.15–3.33)d
1.58 (0.88–2.85)
2.01 (1.16–3.49)e
1.61 (0.88–2.94)
1.78 (0.98–3.23)e
1.32 (0.69–2.53)
6
5
12,324
13,404
49
28
85,746
93,852
0.76 (0.33–1.77)
1.15 (0.44–2.98)
0.73 (0.31–1.74)f
1.10 (0.41–2.92)
0.87 (0.35–2.14)f
1.03 (0.37–2.88)
6
6
12,332
13,404
43
23
85,737
93,852
0.90 (0.38–2.13)
1.66 (0.67–4.07)
0.93 (0.39–2.21)
1.59 (0.63–4.01)
0.88 (0.35–2.18)
1.86 (0.71–4.88)
CCB: calcium channel blockers; CI: confidence interval; CABG/PTCA: coronary artery bypass graft or percutaneous transluminal coronary angioplasty; Mortality: covariate-adjusted relative risks are adjusted for
pre-existing cancer.
a
The relative risk and 95% CI estimates are adjusted for age, multiple drug use, self-reported weight, height, smoking status and mean number of cigarettes smoked per day among women who smoked in 1988,
alcohol intake in 1988, physical activity, menopausal status in 1988, and postmenopausal hormone use.
b
Additional adjustment was made for cholesterol level; systolic and diastolic blood pressure in 1988; aspirin intake; diabetes; and history of stroke, myocardial infarction, CABG/PTCA, angina, and hypertension in
or prior to 1988.
c
Additional adjustment was made for family history of breast carcinoma, history of benign breast disease, age at menarche, parity, age at first birth, and age at menopause.
d
Additional adjustment was made for smoking status and mean no. of cigarettes smoked per day among women who smoked in 1988.
e
Additional adjustment was made for age at the start of smoking.
f
Additional adjustment was made for history of colorectal polyps.
Mortality from total or site specific incident and
prevalent cancers combined did not differ significantly among nurses who reported the use of calcium
channel blockers compared with those who did not
report the use of this drug (Table 2). Of the 335 women
who died of cancer among our study population, 154
were diagnosed with cancer prior to the time of assessment of medication use in 1988, and 181 women
were diagnosed with cancer after 1988.
DISCUSSION
These data do not suggest an important association
between calcium channel blocker use and cancer incidence or cancer mortality. However, we observed an
increase in lung carcinoma incidence among women
who reported the use of calcium channel blockers.
This association remained after statistical adjustment
for smoking status in 1988, amount of smoking in
1988, and age at the start of smoking. Women who
took calcium channel blockers had more pulmonary
disease than women who took other medications.
Since we did not know when these women began
taking calcium channel blockers, pulmonary disease
may or may not have preceded the use of this medication. Controlling for pulmonary disease in the analysis weakened the association somewhat.
Because beta-blockers are contraindicated for patients with pulmonary disease, other medications are
more commonly prescribed for hypertensive patients
with such conditions. In this population, women who
reported regular use of calcium channel blockers in
1988 also reported pulmonary disease prior to 1988
more often than women who used other medications.
It is likely that calcium channel blockers were preferentially prescribed for hypertensive women who also
had pulmonary disease.
We have previously described an excess in the
incidence of myocardial infarction among women
who were smokers and reported the use of calcium
channel blockers.17 A possible interaction between
calcium channel blockers and cigarette smoking could
also underlie the increased incidence of lung carcinoma observed; however, further data are needed to
address this issue.
Calcium Channel Blockers and Cancer/Michels et al.
A number of epidemiologic studies have suggested that hypertension itself may be associated with
cancer mortality and incidence.18,19 In our study population, physician-diagnosed hypertension was not an
important predictor of cancer mortality (RR ⫽ 0.92;
95% CI 0.66 –1.28) or cancer incidence (RR ⫽ 0.94; 95%
CI 0.78 –1.13).
We could not confirm an increased risk of breast
carcinoma for users of calcium channel blockers as
described by Fitzpatrick et al.6 These authors reported
a hazard ratio of 2.57 (95% CI 1.47– 4.49) based on 20
cases of breast carcinoma among women who took
calcium channel blockers and 55 cases among women
who did not take them. Neither Pahor et al.2 nor Jick et
al.4 found significantly elevated relative risks for breast
carcinoma in their site specific cancer analyses.
The current study has a number of limitations. We
had to rely on self-reported medication use, but the
reliability of such data can be assumed to be high
because the study population consists of health professionals. As use of calcium channel blockers was first
assessed in 1988 in this cohort, new and preexisting
prescriptions before 1988 could not be separated. We
further assumed that exposure in 1988 was relevant,
although we had no information on duration of use. If
an extended duration of use was crucial to any association with cancer, exposure may have sometimes
been misclassified and any true effect underestimated.
Since cancer has a considerable latent period, medication use in 1988 or before might be more relevant
than later use. Because we had no information about
the start of medication use, we could not determine
what proportion of women were diagnosed with cancer prior to taking any of the medications.
Similarly, doses of prescriptions were not known.
We had no information on the type of drug within a
particular class. Therefore, we could not study the
association of calcium channel blockers of the dihydropyridine type (e.g., nifedipine) separately from that
of the nondihydropyridines (diltiazem or verapamil).
In conclusion, these prospective data suggest that
a major association between the use of calcium channel blockers of the short-acting formulation and cancer incidence or cancer mortality is unlikely. The elevated risk found for lung carcinoma incidence
deserves further investigation. Further follow-up is
needed to rule out late effects of calcium channel
blockers on cancer risk.
The weight of the current evidence does not give
reason for concern regarding an association between
the use of calcium channel blockers and overall or site
specific cancer incidence or mortality. Although the
incidence of one or the other site specific cancer has
been found to be increased among calcium antagonist
2007
users in some studies, no two studies have found
significant elevations in the incidence of the same
type of cancer.
REFERENCES
1.
2.
3.
4.
5.
6.
6a.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Pahor M, Guralnik JM, Salive ME, Corti MC, Carbonin P,
Havlik RJ. Do calcium channel blockers increase the risk of
cancer? Am J Hypertens 1996;9:695–9.
Pahor M, Guralnik JM, Ferrucci L, Corti MC, Salive ME,
Cerhan JR, et al. Calcium-channel blockade and incidence
of cancer in aged populations. Lancet 1996;348:493–7.
Hardell L, Fredrikson M, Axelson O. Case-control study on
colon cancer regarding previous diseases and drug intake.
Int J Oncol 1996;8:439 – 44.
Jick H, Jick S, Derby LE, Vasilakis C, Myers MW, Meier CR.
Calcium-channel blockers and risk of cancer. Lancet 1997;
349:525– 8.
Trenkwalder PRA, Hendricks P, Hense H-W. Calcium-channel blockers do not increase the risk of fatal or non-fatal
cancer in an elderly European population: results from
STEPHY II. Circulation 1997;96:I–763.
Fitzpatrick AL, Daling JR, Furberg CD, Kronmal RA, Weissfeld
JL. Use of calcium channel blockers and breast carcinoma risk
in postmenopausal women. Cancer 1997;80:1438 – 47.
Rosenberg L, Rao S, Palmer JR, Strom BL, Stolley PD, Zauber
AG, et al. Calcium channel blockers and the risk of cancer.
JAMA 1998;279:1000 – 4.
Daling J. Calcium channel blockers and cancer: is an association biologically plausible? Am J Hypertens 1996;9:713– 4.
Kerr JFR, Wyllie AH, Currie AR. Apoptosis: a basic biological
phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239 –57.
McConkey DJ, Orrenius S. The role of calcium in the regulation of apoptosis. J Leukoc Biol 1996;59:775– 83.
McConkey DJ, Hartzell P, Nicotera P, Orrenius S. Calciumactivated DNA fragmentation kills immature thymocytes.
FASEB J 1989;3:1843–9.
Connor J, Sawczuk IS, Benson MC, Tomashefsky P, O’Toole
KM, Olsson CA, et al. Calcium channel antagonists delay regression of androgen-dependent tissues and suppress gene
activity associated with cell death. Prostate 1988;13:119 –30.
Ray SD, Kamendulis LM, Gurule MW, Yorkin RD, Corcoran
GB. Ca2⫹ antagonists inhibit DNA fragmentation and toxic cell
death induced by acetaminophen. FASEB J 1993;7:453– 63.
Stampfer MJ, Willett WC, Speizer FE, Dysert DC, Lipnick R,
Rosner B, et al. Test of the National Death Index. Am J
Epidemiol 1984;119:837–9.
D’Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson
K, Kannel WB. Relation of pooled logistic regression to time
dependent Cox regression analysis: the Framingham Heart
Study. Stat Med 1990;9:1501–15.
Cox DR. Regression models and life tables. J R Stat Soc
1972;32;187–220.
Rosner B. Fundamentals of biostatistics. 4th edition. Belmont, CA: Duxbury Press, 1995.
Michels KB, Rosner BA, Manson JE, Stampfer MJ, Walker
AM, Willett WC, et al. Calcium channel blockers in relation
to incidence of cardiovascular disease and total mortality
among hypertensive women. Circulation 1998;97:1540 – 8.
Hamet P. Cancer and hypertension. Hypertension 1996;
28:321– 4.
Dyer AR, Stamler J, Berkson DM, Lindberg HA, Stevens E.
High blood pressure: a risk factor for cancer mortality? Lancet 1975;1:1051– 6.
Документ
Категория
Без категории
Просмотров
2
Размер файла
69 Кб
Теги
125
1/--страниц
Пожаловаться на содержимое документа