Older women with high blood pressure taking a Diuretic + ACE Inhibitor were 12% MORE likely to die of cardiovascular disease than those taking NO blood pressure medicines even though their systolic pressure was 16 points LOWER. 1 Tuesday, August 25, 2009
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Older women with high blood pressure taking a
Diuretic + ACE Inhibitorwere 12% MORE likely
to die of cardiovascular disease than those taking
NO blood pressure medicineseven though their systolic pressure
was 16 points LOWER.1Tuesday, August 25, 2009
Hi, this is Larry Hobbs @ FatNews.com
2Tuesday, August 25, 2009
Let me say this the other way.
3Tuesday, August 25, 2009
Women, 50- to 79-years-old...
4Tuesday, August 25, 2009
... with high blood pressure...
5Tuesday, August 25, 2009
... and no history of cardiovascular disease...
6Tuesday, August 25, 2009
... who were NOT taking any drugs for blood pressure...
7Tuesday, August 25, 2009
... were 11% LESS likelyto die of cardiovascular disease...
8Tuesday, August 25, 2009
... during a 5.9 year follow-up...
9Tuesday, August 25, 2009
... than similar women taking aDiuretic +
ACE Inhibitor...
10Tuesday, August 25, 2009
... even though the average systolic pressure
of the women taking NO blood pressure medicines was 16 points HIGHER
than those taking the drug combination.(149 mm Hg vs 133 mm Hg)
11Tuesday, August 25, 2009
This difference may or may not have been statistically significant...
12Tuesday, August 25, 2009
... but, at the very least it suggests that...
13Tuesday, August 25, 2009
... in older women with uncomplicated hypertension...
14Tuesday, August 25, 2009
... giving a Diuretic + ACE Inhibitor does NOT lower the risk
of dying from cardiovascular disease...
15Tuesday, August 25, 2009
... but instead INCREASES the risk.
16Tuesday, August 25, 2009
I realize...
17Tuesday, August 25, 2009
... this is the exact opposite of we have been told.
18Tuesday, August 25, 2009
This is the exact opposite of what we have been led to believe.
19Tuesday, August 25, 2009
But this is exactly what the data shows.
20Tuesday, August 25, 2009
UCLA statistician Sid Port (Lancet, 2000) found that the
widely-held belief that “the lower your blood pressure,
the lower the risk of death”is WRONG.
21Tuesday, August 25, 2009
Sid Port (Lancet, 2000) found the older you are, the higher your systolic pressure can be without
any increased risk in death.
He also found a woman can have a higher systolic pressure than a man of the same age with NO increased risk.
22Tuesday, August 25, 2009
The myth that “the lower your blood pressure, the lower your risk of death” has been perpetuated since 1968 so the drug companies
can sell more drugs.
23Tuesday, August 25, 2009
But the research shows this “sacred” belief is WRONG!
24Tuesday, August 25, 2009
An important lesson to be learned from this is that...
25Tuesday, August 25, 2009
... just because a drug lowers your blood pressure...
26Tuesday, August 25, 2009
... it does NOT necessarily lower your risk of death.
27Tuesday, August 25, 2009
In fact...
28Tuesday, August 25, 2009
... the amount that a drug lowers your blood pressure
is IRRELEVANT!
29Tuesday, August 25, 2009
The ONLY thing that matters is whether or not
these drugs lower your TOTAL RISK OF DEATH.
30Tuesday, August 25, 2009
The same is true for cholesterol-lowering drugs.
31Tuesday, August 25, 2009
The same is true for diabetes drugs.
32Tuesday, August 25, 2009
The ONLY thing that matters is whether or not
these drugs lower your TOTAL RISK OF DEATH.
33Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
34Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
35Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
36Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
37Tuesday, August 25, 2009
reported history of angina (n=3347),myocardial infarction (n=1410), stroke(n=924), angioplasty (n=743), coro-nary artery bypass graft surgery(n=583), or congestive heart failure(n=537). These categories of history ofCVD are not mutually exclusive. We didnot have baseline glucose values; thus,diabetes was defined as self-report of re-ceiving pills or injections for the treat-ment of diabetes. According to this defi-nition, diabetes was present in 1746(5.8%) of women with no history ofCVD and 819 (16.5%) of those withCVD. Of the 30219 women with hy-pertension but no history of CVD,19889 (65.8%) reported they were re-ceiving antihypertensive pharmaco-logical treatment; of these, 920 (4.6%)did not bring in their pills and thus hadno medications recorded in the MDDB,resulting in 18969 women with data re-corded for antihypertensive therapy(FIGURE 1).
Follow-up was for a mean of 5.9 years(interquartile range, 4.9-6.9 years). Wehad minimal loss to follow-up: 94% ofour participants were known to beeither deceased (4.2%) or active (89.7%of participants through August 2003had contact within the previous 15months). Data from those lost to fol-low-up were censored after their lastcontact date. Statistical comparisons ofbaseline characteristics among differ-ent drug groups were determined by !2
test of association between the sub-groups of a particular baseline charac-teristic and the groups receiving mono-therapy or combined therapy with 2classes of drugs. Comparison of con-tinuous variables was performed byanalysis of variance across subgroups.For each end point, prespecified com-parisons of hazard ratios (HRs) fromCox proportional models were per-formed to determine relative risk ofevents for 3 different monotherapy drugclasses compared with diuretic mono-therapy and for 3 combined therapiescompared with a diuret ic plus"-blocker. Multivariate analyses ad-justed for age, race/ethnicity, smok-ing, high cholesterol levels requiringmedication (by self-report), body mass
index (BMI) (calculated as weight in ki-lograms divided by height in meterssquared), physical activity (catego-rized as episodes per week of moder-ate or strenuous activity [defined as ametabolic equivalent tasks score of#4.0 as indicated by Ainsworth et al10]of #20 minutes’ duration), use of hor-mone therapy, and diabetes (definedas a physician diagnosis plus self-reported use of insulin or oral medica-tion). Separate adjusted models werealso run for women without diabetes.
We did not include time-dependentvariables because BP and medicationsdata were only collected at baseline andin year 3. Interaction between effect oftreatment and race (white vs black) wasnot statistically significant. Propor-tional hazards assumptions wereverified by testing the interaction ofsurvival time and treatment and by in-specting parallelism of estimated haz-ard functions. Nominal P values areshown for overall tests of equality
among all drug treatment effects. Con-fidence intervals (CIs) are included toshow specific differences.
Potential confounding by indica-tion was addressed by obtaining a pro-pensity score from a multinomial lo-gistic regression to predict baselinemedication usage from baseline risk fac-tors (age, race/ethnicity, smoking, highcholesterol level requiring medica-tion, prior use of hormone therapy, dia-betes, diastolic and systolic BP, and allpairwise interactions, using stepwise re-gression). These logistic regressionsused pairwise comparisons of the drug-class combinations,11,12 with diuretic asthe reference for monotherapy and di-uretic plus "-blocker as the referencefor combined therapy. For example, todetermine propensity for ACE inhibi-tor plus diuretic vs "-blocker plus di-uretic, the propensity score for the ithparticipant is the conditional probabil-ity Pr{Z=1| Xi=xi}, where Z=1 if ACEinhibitor plus diuretic, 0 if "-blocker
Figure 1. Study Flow
11 294 Receiving Monotherapy
15 787 Receiving Monotherapy WithDiuretic, ACE Inhibitor, β-Blocker,Calcium Channel Blocker, orCombination of These
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
38Tuesday, August 25, 2009
reported history of angina (n=3347),myocardial infarction (n=1410), stroke(n=924), angioplasty (n=743), coro-nary artery bypass graft surgery(n=583), or congestive heart failure(n=537). These categories of history ofCVD are not mutually exclusive. We didnot have baseline glucose values; thus,diabetes was defined as self-report of re-ceiving pills or injections for the treat-ment of diabetes. According to this defi-nition, diabetes was present in 1746(5.8%) of women with no history ofCVD and 819 (16.5%) of those withCVD. Of the 30219 women with hy-pertension but no history of CVD,19889 (65.8%) reported they were re-ceiving antihypertensive pharmaco-logical treatment; of these, 920 (4.6%)did not bring in their pills and thus hadno medications recorded in the MDDB,resulting in 18969 women with data re-corded for antihypertensive therapy(FIGURE 1).
Follow-up was for a mean of 5.9 years(interquartile range, 4.9-6.9 years). Wehad minimal loss to follow-up: 94% ofour participants were known to beeither deceased (4.2%) or active (89.7%of participants through August 2003had contact within the previous 15months). Data from those lost to fol-low-up were censored after their lastcontact date. Statistical comparisons ofbaseline characteristics among differ-ent drug groups were determined by !2
test of association between the sub-groups of a particular baseline charac-teristic and the groups receiving mono-therapy or combined therapy with 2classes of drugs. Comparison of con-tinuous variables was performed byanalysis of variance across subgroups.For each end point, prespecified com-parisons of hazard ratios (HRs) fromCox proportional models were per-formed to determine relative risk ofevents for 3 different monotherapy drugclasses compared with diuretic mono-therapy and for 3 combined therapiescompared with a diuret ic plus"-blocker. Multivariate analyses ad-justed for age, race/ethnicity, smok-ing, high cholesterol levels requiringmedication (by self-report), body mass
index (BMI) (calculated as weight in ki-lograms divided by height in meterssquared), physical activity (catego-rized as episodes per week of moder-ate or strenuous activity [defined as ametabolic equivalent tasks score of#4.0 as indicated by Ainsworth et al10]of #20 minutes’ duration), use of hor-mone therapy, and diabetes (definedas a physician diagnosis plus self-reported use of insulin or oral medica-tion). Separate adjusted models werealso run for women without diabetes.
We did not include time-dependentvariables because BP and medicationsdata were only collected at baseline andin year 3. Interaction between effect oftreatment and race (white vs black) wasnot statistically significant. Propor-tional hazards assumptions wereverified by testing the interaction ofsurvival time and treatment and by in-specting parallelism of estimated haz-ard functions. Nominal P values areshown for overall tests of equality
among all drug treatment effects. Con-fidence intervals (CIs) are included toshow specific differences.
Potential confounding by indica-tion was addressed by obtaining a pro-pensity score from a multinomial lo-gistic regression to predict baselinemedication usage from baseline risk fac-tors (age, race/ethnicity, smoking, highcholesterol level requiring medica-tion, prior use of hormone therapy, dia-betes, diastolic and systolic BP, and allpairwise interactions, using stepwise re-gression). These logistic regressionsused pairwise comparisons of the drug-class combinations,11,12 with diuretic asthe reference for monotherapy and di-uretic plus "-blocker as the referencefor combined therapy. For example, todetermine propensity for ACE inhibi-tor plus diuretic vs "-blocker plus di-uretic, the propensity score for the ithparticipant is the conditional probabil-ity Pr{Z=1| Xi=xi}, where Z=1 if ACEinhibitor plus diuretic, 0 if "-blocker
Figure 1. Study Flow
11 294 Receiving Monotherapy
15 787 Receiving Monotherapy WithDiuretic, ACE Inhibitor, β-Blocker,Calcium Channel Blocker, orCombination of These
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
39Tuesday, August 25, 2009
plus diuretic, and xi is the partici-pant’s baseline covariates (age, race/ethnicity, BMI, etc). Thus, these pro-pensity scores are a composite of theindividual covariates for each person.We then ran Cox regression models us-ing quintiles of propensity scores of theform: event=f(drug class+quintiles ofpropensity scores) to determine the HRof the event for a given monotherapyas compared with diuretic, control-ling for the propensity of that mono-therapy drug in comparison with pro-pensity of diuretic.
We conducted separate Cox regres-sions for each 2-drug–class combina-tion compared with diuretic plus!-blocker, controlling for propensityquintile. These analyses were supple-
mental to the more standard Cox re-gressions controlling for the indi-vidual covariates. Evidence that therewas not overfitting due to colinearityis that the fully adjusted models werein agreement with the propensity scoremodels. Power calculations for com-paring 2 monotherapies for cardiovas-cular death with "=.05 indicate we had90% power to detect a true HR of 1.5,but only 40% power to detect an HR of1.25. All analyses were performed us-ing SAS version 9.0 (SAS Institute Inc,Cary, NC).
RESULTSBaseline CharacteristicsComparisons of baseline characteris-tics of women with hypertension by his-tory of CVD indicate that those with andwithout history of CVD differed sig-nificantly in distributions of demo-graphic characteristics, risk factors, anduse of different antihypertensive drugtherapy classes (TABLE 1 and TABLE 2).Only about one third (35.9%) of womenwith hypertension but no history ofCVD were treated and controlled, andone third had BMIs of 30 or greater.
Among the 18969 women with hy-pertension but no prior history of CVDwho were receiving pharmacologicaltreatment recorded in the MDDB,15787 (83.2%) were treated with ACEinhibitors, !-blockers, calcium chan-nel blockers, or diuretics (n=11294) orwith 1 of the four 2-drug–class combi-nations of these medications (n=4493)(Figure 1). Because the effects of anti-hypertensive drugs on cardiovascularevents may be confounded by cardio-vascular indication for prescribing thesedrugs,9 we assessed baseline character-istics of women with no history of CVDusing the different drug classes(TABLE 3). A greater proportion of thosereceiving calcium channel blockers ordiuretics were black (16.2% and 17.1%,respectively) compared with those re-ceiving ACE inhibitors (7.4%) or!-blockers (4.9%). Baseline systolic BPwas lowest in the diuretic group (135.5mm Hg) and highest in the calciumchannel blocker group (139.2 mm Hg).The drug class with longest duration of
use at baseline was diuretics (7.5 years),while duration of use of ACE inhibi-tors (4.0 years) was similar to that ofcalcium channel blockers (3.6 years).
The group receiving no medica-tions is composed of a mixture of sub-groups (ie, those who may not have hadelevated BPs except at our clinic screen-ing; those who had elevated BP in thephysician’s office but were not pre-scribed medication; and those who wereprescribed medications but did notbring them to their baseline visit to beentered in the medications inventory orreport that they were currently receiv-ing treatment). For this reason, we didnot compare all medication combina-tions with the group receiving no medi-cations, since the results would not havebeen interpretable. We did comparethose receiving no medications withthose receiving diuretics as mono-therapy and found the HRs and 95% CIsfor coronary disease, stroke, and CVDdeath to be, respectively, 0.87 (0.72-1.05), 1.05 (0.77-1.41), and 0.92 (0.63-1.33). The baseline systolic BP of theno medications group was higher (149mm Hg) than for those receiving drugtreatment, but we do not know the BPsof the women who were receivingtherapy before they began the therapy.
Cardiovascular Eventsby TreatmentDuring the mean of 5.9 years of fol-low-up among the 30219 women withhypertension but with no prior historyof CVD, there were 1509 coronary dis-ease events (5.0%), 607 strokes (2.0%),and 406 CVD deaths (1.3%). Among the4979 participants with a prior history ofCVD, there were 945 coronary diseaseevents (19.0%), 234 strokes (4.7%), and245 CVD deaths (4.9%).
Among women with hypertensionbut no history of CVD who were re-ceiving monotherapy, the highest an-nualized rates were for those receiv-ing calcium channel blockers (TABLE 4).Among women receiving combinedtherapy, the highest annualized rateswere for those receiving diuretic pluscalcium channel blocker (stroke andCVD death) and for those receiving
Table 1. Baseline DemographicCharacteristics of Women WithHypertension, by History of CVD*
Characteristic
History of CVD,No. (%)
No(n = 30 219)
Yes(n = 4979)
Age at screening, y50-59 6817 (22.6) 725 (14.6)60-69 14 032 (46.4) 2157 (43.3)70-79 9370 (31.0) 2097 (42.1)
Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CVD, cardiovascular disease.*P$.001 for all comparisons between groups, except for smoking (P=.03).†Calculated as weight in kilograms divided by height in meters squared.
CARDIOVASCULAR OUTCOMES AND ANTIHYPERTENSIVE DRUG TREATMENT IN OLDER WOMEN
Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CVD, cardiovascular disease.*P$.001 for all comparisons between groups, except for smoking (P=.03).†Calculated as weight in kilograms divided by height in meters squared.
CARDIOVASCULAR OUTCOMES AND ANTIHYPERTENSIVE DRUG TREATMENT IN OLDER WOMEN
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Diuretic +ACE
Inhibitor
133 mm Hg
Diuretic + Beta
Blocker
134 mm Hg
Diuretic + Calcium Channel
Blocker
138 mm Hg
ACE Inhibitor + Calcium Channel
Blocker
141 mm Hg
Remember, the average systolic pressure of those taking NO blood pressure
medicine was 149 mm Hg.
42Tuesday, August 25, 2009
ing for the baseline BP and duration re-ceiving baseline medication (data notshown) did not change our results.
CVD Events WithCombined TherapyTABLE 7 compares three 2-drug–classcombinations of antihypertensivetherapy (diuretic plus ACE inhibitor, di-uretic plus calcium channel blocker, andACE inhibitor plus calcium channelblocker) with diuretic plus !-blocker.There were no significant differences be-tween any of these combinations and di-uretic plus !-blocker for coronary heartdisease or for stroke. For CVD death,however, an overall test suggested evi-dence that risk for CVD death con-ferred by combination therapies did dif-fer (P= .05 and P= .002 for the fullyadjusted and nondiabetic models, re-spectively). The combination of di-uretic plus calcium channel blocker wasassociated with an 80% increase, whichincreased to 85% after adjustment for co-variates. Exclusion of women with dia-betes further increased the HR to 2.16(95% CI, 1.16-4.03; P = .002). In analy-ses restricted to the women without dia-betes but with uncomplicated hyper-tension whose systolic BP whilereceiving drug therapy was less than 140mm Hg at baseline, the HR for the com-bination of diuretic plus calcium chan-nel blocker was 2.53 (95% CI, 1.01-6.36). A propensity score (in quintiles)was included in the propensity analy-sis, yielding an HR of 1.83 (95% CI, 1.00-3.36) and indicating an elevated risk ofCVD death with diuretic plus calciumchannel blocker, after accounting for thepropensity to be receiving this drug com-
bination based on the covariates. Noneof the other combined-therapy compari-sons were significant.
justed for age and race/ethnicity plussmoking, high cholesterol level requir-ing medication, BMI, physical activ-ity, use of hormone therapy, and dia-betes for the monotherapy drugs andfor the 2 drug–class combinations. The
Table 5. Risk of Cardiovascular Events Among Women With No History of CVD, byAntihypertensive Monotherapy
*Overall #2 test of whether effects of treatments are equal (ie, all HRs equal unity) from corresponding Cox model.†Adjusted for age and race/ethnicity plus smoking, high cholesterol levels requiring medication, body mass index, physi-
cal activity, use of hormone therapy, and diabetes.‡Adjusted for age and race/ethnicity plus smoking, high cholesterol levels requiring medication, body mass index, physi-
cal activity, and use of hormone therapy.
Table 4. Incident Events and Annualized Rates for Women With Hypertension but No History of CVD (n=30219)
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43Tuesday, August 25, 2009
ing for the baseline BP and duration re-ceiving baseline medication (data notshown) did not change our results.
CVD Events WithCombined TherapyTABLE 7 compares three 2-drug–classcombinations of antihypertensivetherapy (diuretic plus ACE inhibitor, di-uretic plus calcium channel blocker, andACE inhibitor plus calcium channelblocker) with diuretic plus !-blocker.There were no significant differences be-tween any of these combinations and di-uretic plus !-blocker for coronary heartdisease or for stroke. For CVD death,however, an overall test suggested evi-dence that risk for CVD death con-ferred by combination therapies did dif-fer (P= .05 and P= .002 for the fullyadjusted and nondiabetic models, re-spectively). The combination of di-uretic plus calcium channel blocker wasassociated with an 80% increase, whichincreased to 85% after adjustment for co-variates. Exclusion of women with dia-betes further increased the HR to 2.16(95% CI, 1.16-4.03; P = .002). In analy-ses restricted to the women without dia-betes but with uncomplicated hyper-tension whose systolic BP whilereceiving drug therapy was less than 140mm Hg at baseline, the HR for the com-bination of diuretic plus calcium chan-nel blocker was 2.53 (95% CI, 1.01-6.36). A propensity score (in quintiles)was included in the propensity analy-sis, yielding an HR of 1.83 (95% CI, 1.00-3.36) and indicating an elevated risk ofCVD death with diuretic plus calciumchannel blocker, after accounting for thepropensity to be receiving this drug com-
bination based on the covariates. Noneof the other combined-therapy compari-sons were significant.
justed for age and race/ethnicity plussmoking, high cholesterol level requir-ing medication, BMI, physical activ-ity, use of hormone therapy, and dia-betes for the monotherapy drugs andfor the 2 drug–class combinations. The
Table 5. Risk of Cardiovascular Events Among Women With No History of CVD, byAntihypertensive Monotherapy
*Overall #2 test of whether effects of treatments are equal (ie, all HRs equal unity) from corresponding Cox model.†Adjusted for age and race/ethnicity plus smoking, high cholesterol levels requiring medication, body mass index, physi-
cal activity, use of hormone therapy, and diabetes.‡Adjusted for age and race/ethnicity plus smoking, high cholesterol levels requiring medication, body mass index, physi-
cal activity, and use of hormone therapy.
Table 4. Incident Events and Annualized Rates for Women With Hypertension but No History of CVD (n=30219)
NO blood pressure medicines to those taking drugs,
there were 8 comparisons to be made, but...
54Tuesday, August 25, 2009
... the paper only shows one comparison.
55Tuesday, August 25, 2009
They compare women taking NO blood pressure medicines with women taking a diuretic.
56Tuesday, August 25, 2009
But they avoided comparing women taking
NO blood pressure medicines with women taking an
ACE Inhibitor...
57Tuesday, August 25, 2009
They avoided comparing women taking
NO blood pressure medicines with women taking a
Beta Blocker...
58Tuesday, August 25, 2009
They avoided comparing women taking
NO blood pressure medicines with women taking a
Calcium Channel Blocker...
59Tuesday, August 25, 2009
They avoided comparing women taking
NO blood pressure medicines with women taking a
Diuretic + ACE Inhibitor...
60Tuesday, August 25, 2009
They avoided comparing women taking
NO blood pressure medicines with women taking a
Diuretic + Beta Blocker...
61Tuesday, August 25, 2009
They avoided comparing women taking
NO blood pressure medicines with women taking a
Diuretic + Calcium Channel Blocker...
62Tuesday, August 25, 2009
And they avoided comparing women taking
NO blood pressure medicines with women taking anACE Inhibitor +
Calcium Channel Blocker.
63Tuesday, August 25, 2009
So the paper avoided showing 7 of the 8 comparisons.
64Tuesday, August 25, 2009
They said it did not make sense to do these comparisons...
65Tuesday, August 25, 2009
... but I disagree.
66Tuesday, August 25, 2009
I disagree completely.
67Tuesday, August 25, 2009
The only way to find truth...
68Tuesday, August 25, 2009
... is to do all the calculations...
69Tuesday, August 25, 2009
... report whatever the data shows...
70Tuesday, August 25, 2009
... and then try to figure out what it means.
71Tuesday, August 25, 2009
That is the only way to find the truth.
72Tuesday, August 25, 2009
Ignoring the data...
73Tuesday, August 25, 2009
... or trying to explain it away...
74Tuesday, August 25, 2009
... or saying it doesn’t make sense to do the calculations...
75Tuesday, August 25, 2009
... is not how you find the truth.
76Tuesday, August 25, 2009
I can think of two possible reasons
why they avoided doing these comparisons.
77Tuesday, August 25, 2009
The first reason is that...
78Tuesday, August 25, 2009
... these results were the exact opposite of what
they expected.
79Tuesday, August 25, 2009
So they tried to explain it away.
80Tuesday, August 25, 2009
The second reason...
81Tuesday, August 25, 2009
The second reason...
and the one that seems most obvious to me is that...
82Tuesday, August 25, 2009
... two of the coauthors of the paper have taken money from biomedical companies.
83Tuesday, August 25, 2009
One of the authors of the paper, Henry R. Black, MD
Clinical Professor of Internal Medicine and Director of Hypertension
Research at New York University’s School of Medicine...
84Tuesday, August 25, 2009
... has taken money from several drug companies as a consultant and as a speaker.
85Tuesday, August 25, 2009
To me, this is the most likely reason as to why they avoided
doing these comparisons...
86Tuesday, August 25, 2009
... that would have shown that...
87Tuesday, August 25, 2009
... women given these blood pressure drugs were
MORE likely to DIE of Cardiovascular Disease
than women taking NO blood pressure medicine at all.
88Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
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JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
89Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
90Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
at University of California Irvine, on March 26, 2006 www.jama.comDownloaded from
JAMA • Vol 292 • No. 23 • Dec 15, 2004 • pp. 2849-2859
91Tuesday, August 25, 2009
ORIGINAL CONTRIBUTION
Association Between CardiovascularOutcomes and Antihypertensive DrugTreatment in Older WomenSylvia Wassertheil-Smoller, PhDBruce Psaty, MD, PhDPhilip Greenland, MDAlbert Oberman, MD, MPHTheodore Kotchen, MDCharles Mouton, MDHenry Black, MDAaron Aragaki, MSMaurizio Trevisan, MD, MS
DIURETICS OR !-BLOCKERS AREconsidered to be the first stepas monotherapy for highblood pressure (BP), based
on clinical trial results.1 Newer classesof drugs, such as angiotensin-convert-ing enzyme (ACE) inhibitors and cal-cium channel blockers, are also effec-tive in lowering BP and may be moreeffective at lowering BP in particular sub-groups of patients. These newer classesof drugs have increasingly been used asfirst-step monotherapy.2 In 1995, of the10 most frequently prescribed antihy-pertensive drugs, 4 were calcium an-tagonists, 3 were ACE inhibitors, and 1was a !-blocker.3
The Antihypertensive and Lipid-Lowering Treatment to Prevent HeartAttack Trial (ALLHAT) provided clini-cal trial data on monotherapy and in-dicated that diuretics were equal or su-perior to other antihypertensive agentsas first-line therapy.4,5 However, mostpatients with hypertension require morethan 1 drug class to control hyperten-sion.6 It is unresolved as to which of the
Author Affiliations and The Women’s Health Initia-tive Investigators are listed at the end of this article.Financial Disclosures: Dr Psaty has received hono-raria from Celera Diagnostics. Dr Black has servedas a consultant for Astra-Zeneca, Biovail, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis,and Pfizer and has served on the speakers bureau
for Astra-Zeneca, Merck Sharp & Dohme, Novartis,and Pfizer.Corresponding Author: Sylvia Wassertheil-Smoller,PhD, Department of Epidemiology & PopulationHealth, Albert Einstein College of Medicine, Morris ParkAve, Room 1312, Belfer Building, Bronx, NY 10461([email protected]).
Context Diuretic-based therapy is at least as effective as newer classes of agents forhypertension. However, many patients with hypertension require treatment with morethan 1 drug class to achieve blood pressure control. The relative benefits or risks of2-drug–class combinations are not well known.
Objective To prospectively evaluate if there are differences in cardiovascular mor-tality among postmenopausal women with hypertension but no history of cardiovas-cular disease (CVD) treated with different classes of antihypertensive agents, singly orin combination.
Design, Setting, and Participants Women with hypertension enrolled in the Wom-en’s Health Initiative Observational Study, a longitudinal multicenter cohort study of 93676women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years.
Main Outcome Measures Relationship between baseline use of ACE inhibitors,!-blockers, calcium channel blockers, or diuretics, or a combination of these, and in-cidence of coronary heart disease, stroke, and CVD mortality.
Results Among 30 219 women with hypertension but no history of CVD, 11 294(57%) were receiving monotherapy with an ACE inhibitor, !-blocker, calcium chan-nel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combinationof diuretic plus either ACE inhibitor, !-blocker, or calcium channel blocker or ACE in-hibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vsdiuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% con-fidence interval, 1.02-2.35), controlling for multiple covariates. Women treated witha diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vsthose treated with a diuretic plus a !-blocker, after adjustment for age, race, smok-ing, high cholesterol levels requiring medication, body mass index, physical activity,use of hormone therapy, and diabetes. After exclusion of women with diabetes thehazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting forpropensity to be receiving a particular treatment did not change the results. For mor-bid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calciumchannel blockers did not differ from diuretics plus !-blockers.
Conclusions Among women with hypertension but no history of CVD, a 2-drug–class regimen of calcium channel blockers plus diuretics was associated with a higher riskof CVD mortality vs !-blockers plus diuretics. Risks were similar for ACE inhibitors plusdiuretics and !-blockers plus diuretics. Monotherapy with diuretics was equal or superiorto other monotherapy in preventing CVD complications of high blood pressure.JAMA. 2004;292:2849-2859 www.jama.com
! Summary Theoretically, we hu-mans should be better adaptedphysiologically to the diet our an-cestors were exposed to during mil-lions of years of hominid evolutionthan to the diet we have been eatingsince the agricultural revolution amere 10,000 years ago, and since in-dustrialization only 200 years ago.Among the many health problemsresulting from this mismatch be-tween our genetically determinednutritional requirements and ourcurrent diet, some might be a con-sequence in part of the deficiency of potassium alkali salts (K-base),which are amply present in theplant foods that our ancestors ate in abundance, and the exchange ofthose salts for sodium chloride(NaCl), which has been incorpo-rated copiously into the contempo-rary diet, which at the same time ismeager in K-base-rich plant foods.
Deficiency of K-base in the dietincreases the net systemic acid loadimposed by the diet. We know thatclinically-recognized chronic meta-bolic acidosis has deleterious ef-
Received: 10 May 2001Accepted: 23 May 2001
Anthony Sebastian, M. D. (!)Box 0126University of CaliforniaSan Francisco, CA 94143, USATel.: +1-4 15/4 76-11 60Fax: +1-4 15/4 76-09 86E-Mail: [email protected]
fects on the body, including growthretardation in children, decreasedmuscle and bone mass in adults,and kidney stone formation, andthat correction of acidosis canameliorate those conditions. Is itpossible that a lifetime of eating di-ets that deliver evolutionarily su-perphysiologic loads of acid to thebody contribute to the decrease inbone and muscle mass, and growthhormone secretion, which occurnormally with age? That is, are con-temporary humans suffering fromthe consequences of chronic, diet-induced low-grade systemic meta-bolic acidosis?
Our group has shown that con-temporary net acid-producing di-ets do indeed characteristicallyproduce a low-grade systemicmetabolic acidosis in otherwisehealthy adult subjects, and that thedegree of acidosis increases withage, in relation to the normally oc-curring age-related decline in renalfunctional capacity. We also foundthat neutralization of the diet netacid load with dietary supplementsof potassium bicarbonate (KHCO3) improved calcium andphosphorus balances, reducedbone resorption rates, improvednitrogen balance, and mitigated thenormally occurring age-related de-cline in growth hormone secretion– all without restricting dietaryNaCl. Moreover, we found that co-administration of an alkalinizing
salt of potassium (potassium cit-rate) with NaCl prevented NaClfrom increasing urinary calciumexcretion and bone resorption, asoccurred with NaCl administrationalone.
Earlier studies estimated dietaryacid load from the amount of ani-mal protein in the diet, inasmuchas protein metabolism yields sulfu-ric acid as an end-product. Incross-cultural epidemiologic stud-ies, Abelow [1] found that hip frac-ture incidence in older women cor-related with animal protein intake,and they suggested a causal rela-tion to the acid load from protein.Those studies did not consider theeffect of potential sources of basein the diet. We considered that esti-mating the net acid load of the diet(i. e., acid minus base) would re-quire considering also the intake ofplant foods, many of which are richsources of K-base, or more pre-cisely base precursors, substanceslike organic anions that the bodymetabolizes to bicarbonate. In fol-lowing up the findings of Abelow etal., we found that plant food intaketended to be protective against hipfracture, and that hip fracture inci-dence among countries correlatedinversely with the ratio of plant-to-animal food intake. These findingswere confirmed in a more homoge-neous population of white elderlywomen residents of the U. S.
These findings support affirma-
ORIGINAL CONTRIBUTION
L. FrassettoR. C. Morris, Jr.D. E. SellmeyerK. ToddA. Sebastian
Diet, evolution and agingThe pathophysiologic effects of the post-agriculturalinversion of the potassium-to-sodium and base-to-chloride ratios in the human diet
They have found that potassium bicarbonate:• Reduce muscle loss• Reduces bone loss
• Increases growth hormone
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Potassium chloride reduced blood pressure in older people from
160/89 to 145/81 mm Hg.
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Potassium chloride reduced blood pressure in older people from
160/89 to 145/81 mm Hg.
1750-2300 mg of potassium per day lowered systolic pressure by 15 point and