Updates The American Journal of Geriatric Pharmacotherapy

Geriatric Pharmacotherapy Updates

David R.R Guay, P h a r m D

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis,
Minnesota, and Division of Geriatrics, PartneringCare Senior Services, HealthPartners Inc., Minneapolis, Minnesota

W H I C H A S P I R I N DOSES ARE
CARDIOPROTECTIVE?
The findings of a recent systematic review confirm previous assertions that the evidence does not support use
of aspirin dosages greater than 75 to 81 m g / d for the
prevention of cardiovascular (CV) disease. Although
pharmacodynamic data indicate that long-term use of
aspirin dosages as low as 30 m g / d is adequate to fully
inhibit platelet thromboxane production, dosages as
high as 1300 m g / d (taken as 650 BID) are approved
for use. In the United States, the most commonly
prescribed dosage is 81 m g / d (60%), followed by
325 m g / d (35%). The available evidence, mostly from
secondary-prevention studies, suggests that aspirin
dosages exceeding 75 to 81 m g / d do not enhance efficacy but do enhance the risk of hemorrhagic adverse
events, primarily in relation to NSAID gastropathy.
Reference
Campbell CL, Smyth S, Montalescot G, Steinhubl SR.
Aspirin dose for the prevention of cardiovascular disease:
A systematic review. J A M A . 2007;297:2018-2024.
R I V A S T I G H I N E IN H I L D C O G N I T I V E
IHPAIRHENT
In a 4-year trial, patients with mild cognitive impairment were randomized to receive rivastigmine (n =
508) or placebo (n = 510). Progression to Alzheimer's
disease occurred in 1Z3% of rivastigmine recipients
and 21.4% of placebo recipients (hazard ratio [HR] =
0.85; 95% CI, 0.64-1.12; P = NS). The 2 study groups
did not differ significantly in terms of changes from
baseline to end point in standardized Z scores for the
cognitive test battery. Adverse-event frequencies were
similar in the 2 groups (overall adverse events: 95.6%
rivastigmine, 92.7% placebo; serious adverse events:
2Z9% and 30.5%, respectively). As expected, the predominant adverse events were cholinergic in nature.

Accepted for publication October 30, 200Z

Printed in the USA, Reproduction in whole or part is not permitted,

Copyright 2007 Excerpta iVledica,Inc.

Nausea, vomiting, diarrhea, and dizziness occurred

at 2- to 4-fold higher frequencies in the rivastigmine
group compared with the placebo group.
Reference
Feldman HH, Ferris S, Winblad B, et al. Effect of
rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: The InDDEx
study [published correction appears in Lancet Neurol.
2007;6:849]. Lancet Neurol. 2007;6:501-512.
HOHE INTRAVENOUS ANTIHICROBIAL
T H E R A P Y IN O L D E R A D U L T S
Use of home intravenous antimicrobial therapy can be
a viable option for the long-term management of infections in community-dwelling older individuals. From
2000 to 2003, 205 patients from the Veterans Affairs
Ann Arbor Healthcare System received 231 courses
of intravenous antimicrobials; 107 courses in patients
aged >60 years and 124 courses in patients aged
<60 years. In both age groups, the most common indication was osteoarticular infection and the
predominant pathogens were coagulase-positive and
coagulative-negative staphylococci. Older patients were
significantly more likely than younger patients to
require a family member's assistance with the infusions
(35% vs 23%, respectively; P = 0.03) and were more
likely to be seen in urgent care (31.4 vs 14.3 visits per
1000 therapy-days; P < 0.001) or to call the team pharmacist with questions (14.3 vs 8.57 per 1000 therapydays; P = 0.04). Overall, clinical outcomes (efficacy and
toxicity) were similar in both age groups, with a single
exception. Nephrotoxicity (defined as an increase in
serum creatinine of >1 m g / d L or a doubling of the
value from day 1 of outpatient therapy) was significantly more common in the older patients than in the
younger patients (3.03 vs 0.46 per 1000 therapy-days;
P = 0.02).
doi:10,1016/j ,amjopharm .200Z 12.006
1543 5946/$32.00

Volume 5 Number 4

December2007

363

The American Journal of Geriatric Pharmacotherapy

Updates

Reference

Reference

Cox AM, Malani PN, Wiseman SW, Kauffman CA. Home

intravenous antimicrobial infusion therapy: A viable option
in older adults. J A m Geriatr Soc. 2007;55:645-650.
NEW

INDICATION

FOR ZOLEDRONIC

ACID

Based on the results of the H O R I Z O N (Health

Outcomes and Reduced Incidence with Zolcdronic
Acid Once Yearly) trial, zolcdronic acid (Rcclast
[Novartis Pharmaceuticals Corporation, East Hanover,
New Jersey]) has received US F o o d and Drug
Administration (FDA) approval for a new indication,
the treatment ofpostmenopausal osteoporosis. For this
indication, it is administered once annually as 5 mg
IV, infused over 15 minutes. Zolcdronic acid is the
second intravenous bisphosphonatc to receive approval
for this indication. It is not indicated for the prevention of postmcnopausal ostcoporosis. Zolcdronic acid
is available in ready-to-use infusion bottles. The most
common adverse events associated with its use are
fever, flulikc symptoms, myalgias, arthralgias, and
headache (ic, infusion reaction). Most adverse events
occur within 3 days of administration and disappear
within 3 days of onset, although they may last up to
7 to 14 days in some patients. The incidence of infusion
reactions decreases markedly with subsequent doses, so
there is no nccd for preventive medications.
NB: Zomcta (Novartis Pharmaceuticals Corporation), which is used primarily for the treatment of pain
caused by bone metastases and the hypercalcemia of
malignancy, has the same active ingredient as Rcclast.
Zomcta recipients should not receive Rcclast!
ANTIDEPRESSANTS
MINERAL DENSITY

AND

BONE

The prospective Study of Osteoporotic Fractures (SOF)

evaluated the effect of antidepressant therapy on bone
mineral density (BMD) in 2722 older commtmity-dwdling
women (mean age, 78.5 years). Participants were classified
as selective serotonin reuptake inhibitor (SSRI) users (n =
198), tricyclic antidepressant (TCA) users (n = 118), and
antidepressant nonusers (n = 2406). Hip BMD was measured at the sixth and eighth SOF study visits, which took
place a mean of 4.9 years apart. After adjustment for potential confounders, mean total hip BMD decreased by 0.82%,
0.47%, and 0.47% per year in SSRI users, TCA users, and
antidepressant nonusers, respectively (P < 0.001, SSRI users
vs antidepressant nonusers). SSRI users also had higher rates
of bone loss at the 2 hip subregions. The results were not
appreciably altered when women with Geriatric Depression
Scale scores _>6were exduded from the analysis.

364

Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women:
The study of osteoporotic fractures. Arch Intern Med.
2007;167:1240-1245.
The prospective Ostcoporotic Fractures in Men cohort
study evaluated the effect of antidepressant therapy on BMD in 5995 men aged >65 years. In adjusted
cross-sectional data analyses, the mean BMD among
SSRI users (n = 160) was 3.9% lower at the total hip
and 5.9% lower at the lumbar spine compared with that
in antidepressant nonusers (n = 5708) ( P = 0.002 for
total hip; P < 0.001 for lumbar spine). Changes in BMD
among TCA users (n = 99) and trazodonc users (n =
52) did not differ significantly from those in antidepressant nonusers. Adjustment for potential confounders
did not significantly alter the results. The observed difference in BMD in SSRI users was similar to that noted
among recipients of systemic corticosteroids.
Reference

Haney EM, Chan BK, Diem SJ, et al, for the Osteoporotic
Fractures in Men Study Group. Association of low bone
mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007;167:12461251.
Editor's note: The accumulating data regarding
the adverse bone effects of SSRIs are compelling, and
a number of the Bradford-Hill criteria for establishment of causal relationships in observational studies
hold true. Despite some methodologic problems, the
consistency of effects in these 2 studies (both with each
other and with previous studies) and the magnitude of
the associations at least partially support a causal relationship. The finding that the magnitude of the SSRI
effect was similar to that observed with systemic corticosteroids is of clinical concern. As with corticosteroid
prescribing, there is likely to be some unnecessary use
of SSRIs in the general medical community; on the
other hand, there are those who truly need SSRIs and
should receive them despite potential bone concerns.
The indications for initiating and continuing SSRI
therapy require more careful scrutiny in light of their
adverse effects on bone.
THE TRUTH REGARDING ROSIGLITAZONE
AND CARDIOVASCULAR
RISK

A recent meta-analysis of 42 randomized studies of

rosiglitazone with durations of >6 months suggests

Updates The American Journal of Geriatric Pharmacotherapy

that thc risk of myocardial infarction (MI) and dcath

from CV causcs is incrcascd among paticnts taking
rosiglitazone. The mean age of participants in the
42 studics was 56 years and thc mcan basclinc glycosylatcd hcmoglobin (HbAk) value was -8.2%. Thc odds
ratio (OR) for MI in the rosiglitazonc group compared
with the control group was 1.43 (95% CI, 1.03-1.98;
P = 0.03), and the OR for death from CV causes was
1.64 (95% CI, 0.98-2.74; P = 0.06).
Reference

Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N E r ~ I J M e d . 2007;356:2522-2524.

R E C O R D (Rosiglitazonc Evaluated for Cardiac
Outcomcs and Regulation of Glyccmia in Diabctcs) is a
randomizcd, opcn-labcl, noninfcriority trial involving
4447 patients with type 2 diabetes inadequately controllcd by mctformin or a sulfonylurca. An unplanncd
interim analysis of data from the R E C O R D trial
conccntratcd on thc CV safety aspccts of adding rosiglitazonc to mctformin or a sulfonylurca comparcd with
the combination of mctformin plus a sulfonylurca.
Bccausc of a mcan follow-up of only 3.75 ycars at thc
time of the interim analysis, there was limited statistical power to dctcct trcatmcnt differences. An adjudicatcd primary cnd point (hospitalization or dcath from
CV causcs) occurrcd in 217 rosiglitazonc subjccts and
202 control subjccts ( H R = 1.08; 95% CI, 0.89-1.31).
After thc inclusion of cnd points pcnding adjudication,
the H R was 1.11 (95% CI, 0.93-1.32). There wcrc
no significant intcrgroup differences in ratcs of MI,
dcath from CV causcs, or dcath from any causc. However, hcart failure was significantly morc frequent in
rosiglitazone recipients compared with control subjccts ( H R = 2.15; 95% CI, 1.30-3.57) (scc Warnings
section.)
Reference

Home PD, Pocock SJ, Beck-Nielsen H, et al, for the

RECORD Study Group. Rosiglitazone evaluated for
cardiovascular outcomes--an interim analysis. N E r ~ l J
Med. 2007;357:28-38.
Editor's note: At this timc, thc truth about thc
association bctwccn rosiglitazonc and CV risk is not
known. Certainly, thcrc arc wcll-known liabilitics associatcd with rosiglitazonc therapy, including significant
weight gain, adverse effects on serum low-density lipoprotein cholesterol (LDL-C) concentrations, increased
risk of hcart failure (supportcd by thc prcvious study),

and incrcascd risk of fractures in womcn. Given thc

available therapies for diabetes, the clinician should not
bc comfortable using an agcnt that may bc associatcd
with an excess risk for severe CV disease or death from
CV causes. The lack of CV risk data for pioglitazonc is
not particularly reassuring, as we do not know whether
these CV risks arc specific to the individual drug or
are applicable to the entire drug class (ie, both available glitazoncs). Unless further well-designed studics providc convincing cvidcncc of thc CV safety of
rosiglitazone, the analyses reviewed here must be taken
seriously. Ultimately, thc dccision to usc or not usc this
drug will bc madc by paticnts/surrogatcs and thcir
health care providers. It is incumbent on researchers
and drug manufacturers to providc thc highcst-quality
data on which to base this decision.
MORTALITY WITH ANTIPSYCHOTIC
DRUG
USE I N O L D E R A D U L T S W I T H D E M E N T I A

A population-based, rctrospcctive, matched-cohort

study (27,259 matchcd pairs) evaluated thc association bctwccn all-causc mortality and antipsychotic
use in both community-dwelling and institutionalizcd oldcr adults with dcmcntia in Ontario, Canada
(1997-2003). 1 Ncw usc of atypical antipsychotics was
associatcd with a significantly incrcascd risk of mortality at 30 days comparcd with nonusc in both community dwellers (adjusted H R = 1.31; 95% CI, 1.021.70; absolutc risk difference, 0.2 pcrccntagc point)
and institutionalized subjects (adjusted H R = 1.55;
95% CI, 1.15-2.07; absolutc risk difference, 1.2 pcrcentage points). The excess risk appeared to persist
to 150 days, but unequal ratcs of data ccnsoring over
timc may have confounded thc rcsults. Ncw usc of convcntional antipsychotics was associatcd with a highcr
mortality risk at all time points relative to new use of
atypical antipsychotics: at 30 days, the adjusted H R
for convcntional antipsychotics in community dwcllcrs was 1.55 (95% CI, 1.19-2.02; absolute risk diffErence, 1.1 percentage points) and in institutionalized
subjects, was 1.26 (95% CI, 1.04-1.53; absolute risk
difference, 1.1 percentage points). Sensitivity analyses
rcvcalcd that unmcasurcd confounders that incrcasc
the risk of death might diminish or even eliminate the
observed associations.
Editor's note: Although this study had important
limitations, its rcsults arc congrucnt with thosc of
2 previous mcta-analyscsS,3 This study highlights thc
nccd to carefully balancc bcncfit against risk when
considcring antipsychotic usc in oldcr adults with
dementia.

365

The American Journal of Geriatric Pharmacotherapy Updates

References

1. Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic

drug use and mortality in older adults with dementia.
Ann Intern Med. 2007;146:775-786.
2. Kryzhanovskaya LA, Jeste DV, Young CA, et al. A review
of treatment-emergent adverse events during olanzapine
clinical trials in elderly patients with dementia. J Clin
Psychiatry. 2006;67:933-945.
3. Schneider LS, Dagerman KS, Insel P. Risk of death with
atypical antipsychotic drug treatments for dementia:
Meta-analysis of randomized placebo-controlled trials.
JAMA. 2005;294:1934-1943.
DIABETES CARE IN THE NURSING
HOME SETTING

A retrospective chart review of 108 residents with diabetes living in 11 nursing homes in the midwestern United
States found that care failed to meet the American
Diabetes Association (ADA) standards of care for outpatient adults. Although blood glucose (BG) concentrations were monitored in 98% of subjects, only 38% met
BG goals. HbAlc goals were achieved in 67% of subjects.
In the 94% of subjects whose blood pressure (BP) was
monitored, only 55% met BP goals. Lipid concentrations
were checked annually in 31% of subjects, annual electrocardiograms were performed in 37% of subjects, and
urine was checked annually for microalbuminuria in 7%
of subjects. Fifty-two percent of subjects were taking an
angiotensin-converting enzyme inhibitor or angiotensinreceptor blocker, and 42% were taking low-dose aspirin.
Monthly foot examinations were conducted in 87% of
subjects and annual dilated eye examinations in 42% of
subjects. Influenza vaccination was provided annually in
89% of subjects, and at least 1 pneumococcal vaccination
was provided in 46% of subjects.
Editor's note: The failure to meet ADA standards
of care for outpatient adults in this cohort of the institutionalized elderly is not unexpected. The presence
of numerous comorbidities in this population and the
time constraints on health professionals make diabetes
management a complex and difficult task. Perhaps it
is not appropriate to apply the ADA outpatient adult
guidelines to nursing home residents. The time is ripe
for development of guidelines tailored to this patient
population, while the financial implications of such
guidelines would have to be addressed prospectively.

ANTIDEPRESSANT
AUGMENTATION
STRATEGIES IN OLDER ADULTS

It is well known that significant proportions of patients

of all ages do not respond optimally to the initial choice
of antidepressant therapy or even to several subsequent
trials of alternative agents, as a result of either inability
to tolerate the selected agent(s) or biologic heterogeneity of an as-yet unknown etiology. In a study evaluating rates of primary and secondary failure of initial
paroxetine monotherapy combined with interpersonal
psychotherapy and the effect of augmentation therapies
(1, 2, or 3 were allowed, based on the clinical response)
added to the initial antidepressant, 105 of 195 (54%)
older adults (age >70 years) with major depression
responded inadequately to the combination of oral
paroxetine plus interpersonal psychotherapy. Inadequate
response included either an inadequate primary response
(primary failure), which occurred in 77 subjects (73%),
or an initial response followed by early relapse (secondary failure), which occurred in 28 subjects (27%). Sixtynine patients (66%) received augmentation therapy and
36 (34%) did not (primarily because of withdrawal of
consent or comorbidities). The 3 augmentation agents
were sustained-release bupropion (starting at 150 m g / d
for 1 week, followed by titration to a maximum of
400 m g / d based on the response), nortriptyline (titrated
to produce plasma levels of 80-120 ~ag/L), and lithium
(tit_rated to produce plasma levels of 0.5-0.7 m E q / L ) .
The proportions of the 69 patients who received augmentation therapy with 1, 2, or all 3 agents were 68%,
17%, and 14%, respectively. Recovery rates were lower
among those requiring augmentation therapy compared
with those who responded to the initial regimen of
paroxetine plus psychotherapy: 50% in those requiring
augmentation therapy because of an inadequate primary
response and 67% in those requiring augmentation
therapy because of an early relapse, compared with 87%
in those who did not require augmentation therapy (P <
0.001). Those requiring augmentation therapy because
of an inadequate primary response also took significantly
longer to recover (median prolongation, 4 weeks; P =
0.02). A longer time to recovery after the initiation of
augmentation therapy was predicted by the presence of
clinically significant anxiety symptoms (P < 0.05) and a
high general medical burden (P = 0.009).
Reference

Reference

Holt RM, Schwartz FL, Shubrook JH. Diabetes care in

extended-care facilities: Appropriate intensity of care?
Diabetes Care. 2007;30:1454-1458.

366

Dew MA, Whyte EM, Lenze DJ, et al. Recovery from

major depression in older adults receiving augmentation
of antidepressant pharmacotherapy. A m J Psychiatry.
2007;164:892-899.

Updates

VITAMINS, HOMOCYSTEINE,
THROMBOEMBOLISM

AND VENOUS

H O P E - 2 (Heart Outcomes Prevention Evaluation 2)

enrolled 5522 patients aged >55 years with known CV
disease or diabetes and at least 1 other risk factor for
vascular disease. This 5-year study was conducted at
145 sites in 13 countries. Outcomes were compared
in recipients of vitamins (daily folic acid 2.5 mg, vitamin B 6 50 mg, and vitamin B12 1 mg) and placebo.
At the end of the trial, the geometric mean plasma
homocysteine concentration fell by 2.2 ~lmol/L in the
vitamin group and rose by 0.80 ~lmol/L in the placebo
group. Venous thromboembolism (VTE) occurred
in 88 subjects over a mean follow-up of 5 years. The
incidence rate of V T E was the same in both groups
(0.35 per 100 person-years; H R = 1.01; 95% CI, 0 . 6 6 1.53). Vitamin therapy did not reduce the risk of deep
vein thrombosis ( H R = 1.04; 95% CI, 0.63-1.72), pulmonary embolism ( H R = 1.14; 95% CI, 0.57-2.28), or
unprovoked V T E ( H R = 1.21; 95% CI, 0.66-2.23).
Reference

Ray JG, Kearon C, Yi Q, et al, for the Heart Outcomes

Prevention Evaluation 2 (HOPE-2) Investigators.
Homocysteine-lowering therapy and risk for venous
thromboembolism: A randomized trial. A n n Intern
Med. 2007;146:761-76Z

FOLIC ACID FOR STROKE PROPHYLAXIS?

According to results of a meta-analysis of 8 randomized

controlled trials, folic acid supplementation appears to
be an effective strategy for primary prevention (but not
secondary prevention) of stroke. Folic acid supplementation reduced the risk of stroke by 18% (relative risk
[RR] = 0.82; 95% CI, 0.68-1.00; P = 0.045). In stratified analyses, greater beneficial effects were seen when
the duration of treatment was >3 years (RR = 0.71; 95%
CI, 0.57-0.87; P = 0.001), when the plasma homocysteine concentration decreased by >20% (RR = 0.77;
95% CI, 0.63-0.94; P = 0.012), when dietary grain
foodstuffs were not fortified or only partially fortified
with folate (RR = 0.75; 95% CI, 0.62-0.91; P = 0.003),
and when there was no history of previous stroke (RR =
0.75; 95% CI, 0.62-0.90; P = 0.002). In the corresponding comparator groups, the estimated RRs were
attenuated and nonsignificant.
Reference

Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid

supplementation in stroke prevention: A meta-analysis.
Lancet. 2007;369:1876-1882.

The American Journal of Geriatric Pharmacotherapy

G E N I S T E I N IN O S T E O P E N I C
POSTMENOPAUSAL WOMEN

A 2-year, double-blind, placebo-controlled trial conducted in 389 postmenopausal women with osteopenia
has provided positive results for the isoflavone phytoestrogen genistein. At 2 years, BMD had increased in
genistein recipients and decreased in placebo recipients,
both at the lumbar spine (mean change: 0.049 g /
cm 2 [95% CI, 0.035 to 0.059] vs -0.053 g / c m 2 [95%
C I , - 0 . 0 5 8 to -0.035], respectively; mean difference:
0.10 g / c m 2 [95% CI, 0.08 to 0.12]; P < 0.001) and
the femoral neck (mean change: 0.035 g / c m 2 [95%
CI, 0.025 to 0.042] vs - 0 . 0 3 7 g / c m 2 [95% CI, - 0 . 0 4 4
to -0.027]; mean difference: 0.062 g / c m 2 [95% CI,
0.049 to 0.073]; P < 0.001). Genistein also was associated with significant reductions in urinary excretion of
the bone markers pyridinoline and deoxypyridinoline
and increases in levels of bone-specific alkaline phosphatase and insulin-like growth factor I compared with
placebo (range, P < 0.001 to P = 0.002), and did not
significantly affect endometrial thickness. However,
genistein recipients reported gastrointestinal adverse
effects more frequently than did placebo recipients
(19% vs 8%, respectively; P = 0.002), and these effects
led to premature study discontinuation.
Reference

Marini H, Minutoli L, Polito F, et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic
po stmenopausal women: A randomized trial. A n n Intern
Med. 2007;146:839-84Z
HORMONE REPLACEMENT THERAPY IN
POSTMENOPAUSAL WOMEN

The findings of W I S D O M (Women's International

Study of Long Duration Oestrogen After Menopause),
which was the international equivalent of the US
Women's Health Initiative ( W H I ) trial, point to the
deleterious effects of hormone replacement therapy
( H R T ) when initiated long after menopause. This trial
compared estrogen only (conjugated equine estrogens
[CEE] 0.625 m g / d ) with combination hormone therapy (CEE 2.5 m g / d + mcdroxyprogcstcronc acetate
5 mg/d). The trial, which was planned to last 10 years,
was terminated during recruitment (median follow-up,
11.9 months; 6498 woman-years) after publication of
early results from the W H I trial. The mean (SD) age
of patients at randomization to H R T was 62.8 (4.8)
years. When combination hormone therapy (n = 2196)
was compared with placebo (n = 2189), there was a
significant increase in the number of major CV events

367

The American Journal of Geriatric Pharmacotherapy

Updates

(7 vs 0, respectively; P = 0.016) and V T E (22 vs 0;

H R = Z36; 95% CI, 2.20-24.60). There were no
significant differences between groups in terms of the
numbers of women with breast cancer or other cancers,
cerebrovascular events, fractures, or all-cause mortality. No significant differences were found between
estrogen alone and combination hormone therapy.
Reference

Vickers MR, MacLennan AH, Lawton B, et al, for

the WISDOM Group. Main morbidities recorded in
the Women's International Study of long Duration
Oestrogen after Menopause (WISDOM): A randomised
controlled trial of hormone replacement therapy in postmenopausal women. BMJ. 2007;335:239.
CHRONIC OBSTRUCTIVE PULMONARY
DISEASEmMONOTHERAPY,
DOUBLE
THERAPY, OR TRIPLE THERAPY?

Tiotropium, tiotropium-salmeterol, and tiotropiumsalmeterol-fluticasone were compared in 449 patients

with moderate to severe chronic obstructive pulmonary
disease (COPD) over a 1-year period. The proportions of
patients having an exacerbation of COPD did not differ
between tiotropitun alone and tiotropium-salmeterol
(62.8% and 64.8%, respectively; difference: -2.0 percentage points; 95% CI, -12.8 to 8.8) or between tiotropitun
alone and tiotropitun-salmeterol-fluticasone (60.0%; difference: 2.8 percentage points; 95% CI, -8.2 to 13.8).
In sensitivity analyses, point estimates and 95% CIs
shifted in a direction favoring tiotropium-salmeterol and
tiotropium-salmeterol-fluticasone. Compared with tiotropitun alone, tiotropitun-salmeterol-fluticasone was assodated with significant improvements in lung function (P =
0.049) and disease-spedfic quality of life (P = 0.01) and
reduced frequendes of hospitalizations for COPD exacerbations (inddence rate ratio [IRR] = 0.53; 95% CI, 0.33
to 0.86) and all-cause hospitalizations (IRR = 0.67; 95%
CI, 0.45 to 0.99). Tiotropium-salmeterol did not significantly affect hmg function or hospitalization rates compared with tiotropium alone. Thus, the addition of a
long-acting bronchodilator and a corticosteroid to anticholinergic monotherapy was associated with benefits in
terms of lung function, quality of life, and hospitalization
rates for COPD exacerbations.
Reference

Aaron SD, Vandemheen KL, Gergusson D, et al, for

the Canadian Thoracic Society/Canadian Respiratory
Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol

368

for treatment of chronic obstructive pulmonary disease:

A randomized trial. A n n Intern Mad. 2007;146:545555.
B E N E F I T S OF A G G R E S S I V E S T A T I N
THERAPY IN OLDER PATIENTS

The T N T (Treating to New Targets) study compared

low- and high-dose statin therapy in 10,001 patients
between the ages of 35 and 75 years who had coronary heart disease ( C H D ) and L D L - C concentrations
<130 m g / d L . A prespecified secondary analysis of
the T N T study included data from 3809 patients who
were aged >65 years at study entry. In the comparison
of atorvastatin 10 and 80 m g / d , high-dose therapy
was associated with a 2.3% reduction in absolute risk
and a 19% reduction in RR for the composite primary
end point of major CV events ( H R = 0.81; 95% CI,
0.67-0.98; P = 0.032). Numeric but nonsignificant
reductions were observed in high- versus low-dose
statin recipients for the following components of the
composite end point: mortality rates from C H D , nonfatal non-procedure-related MI, and fatal or nonfatal
stroke (ischemic, embolic, hemorrhagic, or unknown).
The effects of therapy on both primary and secondary efficacy end points, as well as adverse-event outcomcs, did not differ significantly between thosc agcd
>65 ycars and thosc agcd <65 ycars. Thc bcncfits of
high-dosc statin thcrapy in thc oldcr paticnts wcrc not
obtained at the cost of persistent elevations in creatine
phosphokinase concentrations.
Reference

Wenger NK, Lewis SJ, Herrington DM, et al, for the

Treating to New Targets Study Steering Committee
and Investigators. Outcomes of using high- or low-dose
atorvastatin in patients 65 years of age or older with stable coronary heart disease. A n n Intern Mad. 2007;147:
1-9.
ANTIOXIDANTS
TO PREVENT
CARDIOVASCULAR EVENTS IN WOMEN

In WACS (Women's Antioxidant Cardiovascular

Study), 8171 women health professionals aged
>40 years with a history of CV disease or at least 3 risk
factors for CV disease were randomized to receive
ascorbic acid 500 m g / d , vitamin E 600 IU Q O D ,
beta-carotene 50 mg Q O D , or placebo, either alone or
in various combinations (8 study groups). The median
duration of follow-up was 9.4 years. The primary end
point was a combination of MI, stroke, coronary revascularization, and CV death. A total of 1450 women

Updates

experienced _>1 CV disease outcome. In the study

population as a whole, ascorbic acid had no significant
effect on the primary end point (RR = 1.02; 95% CI,
0.92-1.13), nor did vitamin E (RR = 0.94; 95% CI,
0.85-1.04) or beta-carotene (RR = 1.02; 95% CI,
0.92-1.13). None of the 3 agents had a significant
effect on any of the secondary outcomes (ie, the individual components of the primary end point) in the
study population as a whole. Vitamin E was associated
with a significant reduction in the primary end point in
the prespecified subgroup of women with previous CV
disease (RR = 0.89; 95% CI, 0.79-1.00; P = 0.04; P for
the interaction = NS). There were no significant 2- or
3-way interactions between agents for the primary end
point; however, women randomized to receive ascorbic
acid and vitamin E had fewer strokes (RR = 0.69; 95%
CI, 0.49-0.98; P = 0.04; P value for the interaction =
0.03). The only significant relationship with an adverse
event was seen among beta-carotene recipients, who
had a small increase in symptoms suggestive of gastric
upset (RR = 1.06; 95% CI, 1.00-1.11; P = 0.05).
Editor's note: This trial adds to the negative findings for antioxidants in the prophylaxis of CV disease.
This trial evaluated whether these agents would produce a positive effect in women, and the answer was
an unequivocal no.

The American Journal of Geriatric Pharmacotherapy

Reference

Kahler KH, Rajan M, Rhoads GG, et al. Impact of

oral antihyperglycemic therapy on all-cause mortality
among patients with diabetes in the Veterans Health
Administration. Diabetes Care. 2007;30:1689-1693.
ANTITHROMBOTIC
THERAPY FOR
NONVALVULAR
ATRIAL FIBRILLATION

A 29-study meta-analysis involving 28,044 mostly older

patients found that warfarin was 40% more effective than
antiplatelet therapies for stroke prevention in patients
with nonvalvular atrial fibrillation. Adjusted-dose warfarin (6 trials, 2900 patients) and antiplatelet agents
(8 trials, 4876 patients) reduced the risk of stroke by
64% (95% CI, 49-74) and 22% (95% CI, 6-35), respectively, compared with controls. Adjusted-dose warfarin
(12 trials, 12,963 patients) was significantly more effEctive than antiplatelet agents (RR reduction = 39%;
95% CI, 22-52). Other comparisons were inconclusive.
Absolute increases in the risk for major extracranial
bleeding were small (0.3% per year).
Reference

Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who
have nonvalvaalaratrial fibrillation. A n n Intern Med. 2007;
146:857-867.

Reference

Cook NR, Albert CM, Gaziano JM, et al. A randomized

factorial trial of vitamins C and E and beta carotene in the
secondary prevention of cardiovascular events in women:
Results from the Women's Antioxidant Cardiovascular
Study. Arch Intern Med. 2007;167:1610-1618.
ALL-CAUSE MORTALITY
ORAL HYPOGLYCEMICS
ANTIHYPERGLYCEMICS

WITH
AND

A retrospective analysis of data from the Veterans

Health Administration (VHA) Diabetes Epidemiology
C o h o r t examined the effect of various oral agents
for type 2 diabetes on rates of all-cause mortality
(N = 39,721). The adjusted ORs (AORs) for all-cause
mortality were 0.87 for metformin monotherapy users
(95% CI, 0.68-1.10), 0.92 for metformin + sulfonylurea users (95% CI, 0.82-1.05), and 1.04 for glitazone
monotherapy users (95% CI, 0.75-1.46), all relative to
sulfonylurea monotherapy users, for whom the A O R
was fixed at 1.0. The A O R for no drug users was 0.90
(95% CI, 0.74-1.09). Thus, no significant drug effect
on all-cause mortality was found relative to sulfonylurea monotherapy in this V H A patient database.

W H A T IS T H E A N T I T H R O M B O T I C
OF
CHOICE IN THE OLDEST PATIENTS WITH
ATRIAL FIBRILLATION?

The BAFTA (Birmingham Atrial Fibrillation Treatment

of the Aged) study set out to determine the best antithrombotic for patients aged _>75 years. Warfarin, dosed
to provide an international normalized ratio (INR) of 2 to
3, was found to provide greater protection against stroke
than aspirin 75 m g / d without significantly increasing the
bleeding risk. Warfarin recipients had 24 primary events
(21 strokes, 2 other intracranial hemorrhages, 1 systemic
embolus), and aspirin recipients had 48 primary events
(44 strokes, 1 other intracranial hemorrhage, 3 systemic
emboli). The respective yearly event risks were 1.8% and
3.8% (RR = 0.58 [95% CI, 0.28 to 0.80], P = 0.003;
absolute yearly RR = 2% [95% CI, 0.7 to 3.2]). The yearly
extracranial hemorrhage risks were 1.4% and 1.6%
(RR = 0.87 [95% CI, 0.43 to 1.73]; absolute yearly
RR = 0.2% [95% CI, -0.7 to 1.2]).
Reference

Mant J, Hobbs FD, Fletcher K, et al, for the BAFTA

Investigators, Midland Research Practices Network

369

The American Journal of Geriatric Pharmacotherapy

Updates

(MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial
fibrillation (the Birmingham Atrial Fibrillation
Treatment of the Aged Study, BAFTA): A randomised controlled trial. Lancet. 2007;370:493503.

IS T H E R E A C L I N I C A L L Y S I G N I F I C A N T
DRUG-DRUG
INTERACTION
BETWEEN
CLOPIDOGREL AND STATINS?

Theoretical concerns and ex vivo results have suggested a potential detrimental interaction between
clopidogrel and statins metabolized by the cytochrome
P450 (CYP) 3A4 isozyme. Data from the CHARISMA
(Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management, and Avoidance)
trial were analyzed to determine whether similar
concerns arose in vivo in humans. When data for
statins that are metabolized primarily by CYP3A4
(atorvastatin, lovastatin, and simvastatin [ALS]) were
compared with data for other statins (pravastatin and
fluvastatin [PF]), similar outcomes were observed in
patients receiving A l S or PF who were also receiving
long-term clopidogrel 75 m g / d . O f 15,603 enrollees,
10,078 received a statin at baseline (8245 ALS,
1748 PF) and 5496 did not (patient numbers as
reported). At a median follow-up of 28 months, the
primary end point (a composite of MI, stroke, or CV
death) occurred in 6.8% of clopidogrel recipients and
7.3% of placebo recipients in the overall population
( H R = 0.93; P = 0.22). The frequency of the primary
end point was also similar whether atorvastatin or
pravastatin was administered with clopidogrel. The
interaction between atorvastatin or pravastatin and
randomized treatment was nonsignificant. Thus, there
appears to be no clinically significant detrimental interaction between clopidogrel and statins metabolized by
CYP3A4.
E d i t o r ' s note: Most laboratory-based studies have
found no interaction between clopidogrel and statins
metabolized by CYP3A4, nor was any interaction
noted in this in vivo study in humans. There is no
need to select statins for clopidogrel recipients on the
basis of CYP3A4 metabolism.
Reference

Saw J, Brennan DM, Steinhubl SR, et al, for the

CHARISMA Investigators. Lack of evidence of a
clopidogrel-statin interaction in the CHARISMA trial.
J A m Coil Cardiol. 2007;50:291-295.

370

ARE THERE RACIAL DIFFERENCES IN

BLEEDING RISK WITH WARFARIN IN
PATIENTS WITH ATRIAL FIBRILLATION?

In an analysis of racial/ethnic differences in crude event

rates for warfarin-related intracranial hemorrhage (ICH)
that used combined pharmacy and laboratory data from
the Kaiser Permanente Southern California health maintenance organization, this adverse event occurred more
frequently in nonwhites (including blacks, Hispanics,
and Asians) than in whites. Between 1995 and 2000,
18,867 qualifying atrial fibrillation hospitalizations
were identified (78.5% white, 8.0% black, 9.5% Hispanic,
3.9% Asian); 173 qualifying I C H events occurred over
a mean of 3.3 years of follow-up. The anticoagulation
intensity achieved was significantly lower among blacks
compared with all other groups (P < 0.001) and did
not differ between the other groups. Warfarin use was
associated with an increased I C H risk in all races, but
the magnitude of risk was greatest among nonwhites.
There were no sex-related differences. Using whites
as the reference, the H R for I C H was 4.06 for Asians
(95% CI, 2.47-6.65), 2.06 for Hispanics (95% CI,
1.31-3.24), and 2.04 for blacks (95% CI, 1.25-3.35).
Known risk factors for I C H (advanced age, hypertension, and anticoagulation intensity) were similar in the
racial groups and did not explain the excessive risk of
I C H observed in nonwhites. However, because the
study examined hypertension as a dichotomous variable
(present/absent), there was no adjustment for stage of
hypertension or adequacy of BP control. Other factors
known to affect I C H risk (eg, alcohol or illicit drug use)
and drug interactions between over-the-counter/herbal
medications and warfarin could not be assessed. Also,
day-to-day fluctuations in anticoagulation intensity, a
possible explanation for the observed racial differences,
were not assessed.
Reference

Shen AY, Yao IF, Brar SS, et al. Racial/ethnic differences

in the risk ofintracranial hemorrhage among patients with
atrial fibrillation. J A m Coil Cardiol. 2007;50:309-315.
THROMBOEMBOLISM
PROPHYLAXIS
PERIPHERAL ARTERIAL DISEASE

IN

In WAVE (Warfarin Antiplatelet Vascular Evaluation),

combination anticoagulant/antiplatelet therapy was
no more effective than antiplatelet therapy alone
in preventing major CV complications. However,
it was associated with an increased risk for lifethreatening bleeding. Two thousand one hundred sixtyone patients were randomized to receive an anticoagu-

Updates The AmericanJournal of Geriatric Pharmacotherapy

lant (warfarin or accnocoumarol; target INR, 2.0-3.0)

plus antiplatclct therapy (aspirin 81-325 m g / d , ticlopidine, or clopidogrel) or antiplatelet therapy alone. The
mean duration of follow-up was 35 months. MI, stroke,
or death from CV causes occurred in 132 of 1080
(12.2%) recipients of combination therapy and 144 of
1081 (13.3%) recipients of antiplatelet monotherapy
(RR = 0.92; 95% CI, 0.73-1.16; P = NS). MI, stroke,
severe ischemia, or death from CV causes occurred in
172 (15.9%) and 188 (1Z4%) of the respective groups
(RR = 0.91; 95% CI, 0.74-1.12; P = NS). Lifethreatening bleeding, which was defined as fatal or
intracranial bleeding or bleeding requiring surgical
intervention or transfusion of at least 4 units of blood
a n d / o r blood products, including fresh-frozen plasma,
occurred in 43 (4.0%) and 13 (1.2%) of combinationtherapy and antiplatelet-monotherapy recipients, respectively (RR = 3.41; 95% CI, 1.84-6.35; P < 0.001).

women (age <60 years) and detrimental CV effects in

older postmenopausal women (age >60 years). Two
ongoing studies--KEEPS (Kronos Early Estrogen
Prevention Study) and ELITE (Early Versus Late
Intervention Trial with Estradiol)--will provide additional data regarding this hypothesis. It is important
to continue emphasizing that H R T should not be considered a preventive therapy for CV disease in women,
even in those who are postmenopausal and aged
<60 years, until more data are available for review.

Reference

Based on a careful and thorough systematic review

conducted by investigators in the field of CV medicine, the following key points can be made regarding
clopidogrel use.
1. Clopidogrel monotherapy is nominally superior
to aspirin for reducing ischemic vascular events in
high-risk patients. It has improved gastrointestinal
tolerability but is associated with excess rash, diarrhea,
and adverse hematologic outcomes (eg, thrombotic
thrombocytopenic purpura, neutropenia).
2. Compared with aspirin alone, the combination
of clopidogrel + aspirin is beneficial in high-risk patients (ie, those with unstable angina a n d / o r n o n ST-elevation MI [UA/NSTEMI], ST-elevation MI
[STEMI], and stenting). Long-term benefit is driven
by reductions in nonfatal MI, but there is little impact
on stroke or death. Major bleeding complications are
increased.
3. Compared with clopidogrel alone, the combination of clopidogrel + aspirin has no benefit in terms
of reducing ischemic stroke. Major bleeding complications are increased.
4. Randomized controlled trials comparing clopidogrcl and ticlopidinc have found no major differences
in efficacy/tolerability. Nonrandomized studies found
an increase in hematologic adverse events with ticlopidine. Ticlopidine is less expensive than clopidogrel,
but clopidogrel is better tolerated and more convenient
(once-daily dosing).
5. In clinical practice, long-term use of dopidogrel
appears to have no benefit and is associated with
an excess risk of moderate bleeding in patients with

Anand S, Yusuf S, Xie C, et al, for the Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral
anticoagulant and antiplatelet therapy and peripheral
arterial disease. N EnglJ Med. 2007;357:217-22Z
IS E S T R O G E N T H E R A P Y B E N E F I C I A L
IN PREVENTING CORONARY
ARTERY CALCIFICATION
IN YOUNG
POSTHENOPAUSAL
WOHEN?

In a subanalysis of the W H I study, the effects of CEE

0.625 m g / d and placebo on coronary artery calcification were compared in 1064 women who had undergone hysterectomy and wore aged between 50 and
59 years at randomization. The mean coronary artery
calcium score after completion of the trial was significantly lower in estrogen recipients compared with placebo recipients (83.1 vs 123.1, respectively; P = 0.02).
After adjustment for coronary risk factors, the ORs for
coronary artery calcium scores of >0, >10, and >100 in
estrogen versus placebo recipients wore 0.78 (95% CI,
0.58-1.04), 0.74 (0.55-0.99), and 0.69 (0.48-0.98),
respectively. The corresponding ORs for women who
were at least 80% adherent to the assigned therapy were
0.64 (P= 0.01), 0.55 (P< 0.001), and 0.46 (P= 0.001).
For coronary artery calcium scores >300 relative to
scores <10, the OR was 0.58 by intention-to-treat
analysis (P = 0.03) and 0.39 in women with at least
80% adherence (P = 0.004).
Editor's note: These results lend support to the timing hypothesis, which suggests that H R T has potentially beneficial CV effects in young postmenopausal

Reference

Manson JE, Allison MA, Rossouw JE, et al, for the

WHI and WHI-CAGS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med.
2007;356:2591-2602.
CLOPIDOGREL
DISEASE

IN CARDIOVASCULAR

371

The American Journal of Geriatric Pharmacotherapy

Updates

stable CV disease; thus, such use is not recommended.

Clopidogrel may be used for 1 to 9 months in highrisk patients with UA/NSTEMI who are at low risk for
bleeding. It may be used for _>1 month with lytic therapy
in patients with STEMI. (There have been no direct
studies in patients with primary percutaneous coronary
intervention [PCI]). Clopidogrel may be used for up to
1 month with bare metal stents and for a longer period
(_>6months) with drug-eluting stents in patients with PCI.
6. Use of clopidogrel is not recommended as firstline therapy for patients with cerebrovascular accident,
unless there is a clear indication for clopidogrel (eg,
acute coronary syndrome or stent placement).
Z Preintervention (PCI, coronary artery bypass
grafting [CABG]) treatment with clopidogrel appears
to have no definite benefit. In addition, there is an
increased bleeding risk associated with CABG.
8. Clopidogrel therapy should be stopped at least
5 days and preferably 7 days before elective CABG and
other surgical procedures.
9. Adjunctive use of clopidogrel with glycoprotein
IIb/IIIa inhibitors is effective and safe at a 600-mg dose
in high-risk patients with acute coronary syndromes.
10. The definition, prevalence, diagnosis, mechanism, and clinical relevance of clopidogrel resistance
are unclear.
Reference

Eshaghian S, Kaul S, Amin S, et al. Role of clopidogrel

in managing atherothrombotic cardiovascular disease.
A n n Intern Med. 2007;146:434-441.
HEPARIN-INDUCED
THROMBOCYTOPENIA
AT A TEACHING HOSPITAL

A retrospective review of recipients ofheparin and direct

thrombin inhibitor (DTI) therapy was conducted using
hospital records for a 1-year period at a large tertiarycare hospital. Among 58,814 patient admissions, an
estimated 24,068 patients were exposed to unfractionated heparin, and 133 patients received DTI therapy.
Among the latter, 49 new cases of heparin-induced
thrombocytopenia (HIT) and 15 cases of suspected
(but unconfirmed) HIT were identified. The overall
incidence of newly recognized HIT was 0.2%. New
cases of HIT occurred in 0.76% of patients receiving
therapeutic doses of intravenous heparin and <0.1% of
patients receiving antithrombotic prophylaxis with subcutaneous heparin. Forty-nine percent of all new cases
of HIT occurred in patients undergoing CABG and/or
valve replacement surgery, whereas no cases occurred in
patients undergoing hip or knee arthroplasty.

372

Reference

Smythe MA, Koerber JM, Mattson JC. The incidence of recognized heparin-induced thrombocytopenia in a large, tertiary care teaching hospital. Chest.
2007;131:1644-1649.
PROTON PUMP INHIBITORS AND ADVERSE
CARDIOVASCULAR
EVENTS

In earlier communications, the FDA raised concerns

about the CV safety of long-term omeprazole and
esomeprazole therapy. In 2 small long-term studies,
one with each drug, patients were randomized to proton pump inhibitor (PPI) therapy or surgical therapy
for gastroesophageal reflux disease. The results of the
studies suggested that long-term PPI therapy may
increase the risk for MI, heart failure, and sudden cardiac death compared with surgical therapy. After
reviewing these and other data submitted by the
manufacturer of omeprazole and esomeprazole, the
FDA's preliminary conclusion was that the collective
data did not suggest an increased risk for adverse CV
events in long-term recipients of these 2 PPIs. No
change in the prescribing or utilization of these products is warranted at this time.
Reference

Early communication about an ongoing safety review:

Omeprazole (I'rilosec), esomeprazole (Nexium). http://
www.fda.gov/cder/drug/early_comm/omeprazole_
esomeprazole.htm. Accessed November 3, 2007.
ANTIDIABETIC
AGENTS IN PATIENTS WITH
DIABETES AND HEART FAILURE

To date, only the thiazolidinediones (glitazones) have

been linked definitively with the precipitation or worsening of heart failure in patients with diabetes. The
results of a recent systematic review provide additional
quantitative data for insulin, metformin, and the glitazones in patients with diabetes and heart failure. Eight
studies were included in the review. In 3 of 4 studies
involving insulin, insulin use was associated with a 25%
to 242% increased risk for all-cause mortality. In 2 of
these 4 studies, the ORs (unadjusted for diet and other
antidiabetic drug use) were 1.25 (95% CI, 1.03-1.51)
and 3.42 (95% CI, 1.40-8.37), respectively; in the
other 2 studies, the HRs (adjusted for diet and other
antidiabetic drug use) were 1.66 (95% CI, 1.20-2.31)
and 0.96 (95% CI, 0.88-1.05), respectively. Metformin
was associated with significant 14% to 30% reductions
in all-cause mortality in 2 studies (HR = 0.86 [95%
CI, 0.78-0.97] vs other antidiabetic drugs and insulin;

Updates The AmericanJournal of Geriatric Pharmacotherapy

H R = 0.70 [95% CI, 0.54-0.91] vs sulfonylureas). A

similar pattern was seen in a third study of metformin.
M e t f o r m i n was not associated with increased hospital
admissions for heart failure or for any other cause. In
4 studies, the use of glitazones was associated with
a 17% reduction in all-cause mortality (pooled O R =
0.83; 95% CI, 0.71-0.97; P = 0.02). However, glitazone use was associated with a 13% increase in risk of
hospital admission for heart failure (pooled O R = 1.13;
95% CI, 1.04-1.22; P = 0.004). The 2 studies involving
sulfonylureas had conflicting results, probably because
of differences in the comparator treatments. It should
be noted that all 8 studies had important limitations.
Reference

Eurich DT, McAlister FA, Blackburn DF, et al. Benefits

and harms of antidiabetic agents in patients with diabetes and heart failure: Systematic review. BMJ. 2007;
335:49Z
CALCIUM AND VITAMIN D DOSES FOR
OSTEOPOROTIC
FRACTURES

A mcta-analysis of 29 randomized trials including a

total of 63,897 subjects evaluated the use of calcium or
calcium + vitamin D supplementation to prevent fractures and bone loss in people aged >50 years. In the
17 trials that reported fracture as an outcome (n =
52,625), treatment with calcium and vitamin D was
associated with a 12% reduction in fractures of all types
(risk ratio = 0.88; 95% CI, 0.83-0.95; P < 0.001). In
the 23 trials that reported B M D as an outcome (n =
41,419), treatment with calcium and vitamin D was
associated with an 0.54% reduction in the rate of bone
loss at the hip (95% CI, 0.35-0.73; P < 0.001) and a
1.19% reduction in the rate of bone loss in the spine
(95% CI, 0.76-1.61; P < 0.001). The fracture risk
reduction was 24% greater in trials in which compliance was _>80% (P < 0.001). The treatment effect was
greater with an elemental calcium dosage _>1200 m g / d
compared with <1200 m g / d (risk ratio = 0.80 vs
0.94, respectively; P = 0.006) and a vitamin D dosage
_>800 I U / d compared with <800 I U / d (risk ratio =
0.84 vs 0.87, respectively; P = 0.03). Thus, in patients
aged _>50 years who are at risk for osteoporotic fractures, the elemental calcium dose should be at least
1200 r a g / d ; if vitamin D is needed, the dose should be
at least 800 I U / d .
Reference

Tang BM, Eslick GD, Nowson C, et al. Use of calcium or

calcium in combination with vitamin D supplementation

to prevent fractures and bone loss in people aged 50 years

and older: A meta-analysis. Lancet. 2007;370:657-666.
IS V I T A M I N

D A LIFE SAVER?

A recent mcta-analysis evaluated 18 randomized controlled trials of vitamin D supplementation that enrolled
a total of 57,311 participants and involved 4777 allcause deaths over a mean study follow-up period of
5.7 years. In the 9 trials that measured serum concentrations of the active vitamin D metabolite, there was
a 1.4- to 5.2-fold difference in serum concentrations
of 25-hydroxyvitamin D 3 between the intervention
(vitamin D supplementation) and control groups. The
summary R R for death from any cause was 0.93 (95%
CI, 0.87-0.99), representing a significant (although
modest) 7% reduction in mortality in recipients of
vitamin D. There was no indication of statistical heterogeneity or publication bias. Calcium supplementation did not alter the s u m m a r y R R for vitamin D
supplementation.
E d i t o r ' s note: These data raise a number of questions. Could the 7% mortality reduction be increased
by higher vitamin D intake, higher serum 25-hydroxyvitamin D concentrations, a longer period of supplementation, or improved adherence? Which causes of
death accounted for the reduced mortality? What were
the mechanisms of this benefit? Was the mortality reduction seasonal (ic, primarily in winter, when vitamin D
levels typically fall)? Certainly, further research is needed
to elucidate the specific benefits and the optimal intake
and serum metabolite concentrations. Nonetheless, a
more proactive approach to the identification, prevention, and treatment of vitamin D deficiency should
become a component of routine medical care.
Reference

Autier P, Gandini S. Vitamin D supplementation and

total mortality: A meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1730-173Z
FIRST APPROVED PRESCRIPTION
ADHERENCE DEVICE

O n June 21, 2007, the F D A approved E M M A

(Electronic Medication M a n a g e m e n t Assistant,
I N R a n g e Systems, Inc., Altoona, Pennsylvania), a programmable storage and dispensing device for use in the
h o m e setting. This computerized medication box was
designed for use under the supervision of a licensed
health care provider. The FDA felt that this device
could be particularly useful for older patients and
those taking complex regimens (eg, those infected with

373

The American Journal od"Geriatric Pharmacotherapy Updates

HIV). The device is categorized as a remote medication managcmcnt systcm in Class II (spccial controls).
Reference

US Food and Drug Administration, HHS. Medical

devices; general hospital and personal use devices; classification of remote medication management system.Final
rule. Fed Regist. 2007;72:59175-59177.
PHARMACOGENOMICS
THE CLINIC

REACHES

"Personalized medicine," in which prescribers take the

pharmacokinetic/pharmacodynamic effects of an individual's genetics into account, has finally entered the
clinic. For the first time, pharmacogenomic information
is cited in the prescribing information for a widely used
drug. The labeling for warfarin now contains information regarding the effects of variation in 2 genes,
onc affecting warfarin mctabolism (CYP2C9) and thc
othcr affecting its pharmacodynamics (VKORC1). Thc
revised product labeling provides guidance on how to
apply this information. Ongoing thcrapy should always
be guided by continued monitoring of the INR.

lcast 1 dictary supplcmcnt or CAM previously rcportcd

to interact with warfarin. Usc of warfarin for <3 months
was thc only significant risk factor for suprathcrapcutic
INR values (OR = 2.90; 95% CI, 1.10-7.63). Thc
dictary supplcmcnts/CAM that wcrc associatcd with an
incrcascd sclf-rcportcd blccding risk includcd cayenne
(OR = 8.0; 95% CI, 3.57-17.92), gingcr (OR = 6.63;
95% CI, 3.49-12.61), willow bark (OR = 9.0; 95%
CI, 6.42-12.62), St. John's wort (OR = 4.7; 95% CI,
1.19-14.79), and cocnzymc Q10 (OR = 3.91; 95% CI,
2.09-7.31). Concurrcnt usc of >1 dictary supplement/
CAM was another risk factor for self-reported bleeding
(OR = 2.11; 95% CI, 1.074.16). In thc fully adjusted
multivariate model, dietary supplements/CAM that
wcrc independently associated with an increased risk for
sclf-rcportcd blccding includcd cocnzymc Q10 (OR =
3.69; 95% CI, 1.88-7.24) and gingcr (OR = 3.20; 95%
CI, 2.424.24). Other risk factors significantly associatcd with blccding includcd a high targct INR (2.53.5) (OR = 2.49; 95% CI, 1.24-5.00), diarrhca (OR =
1.61; 95% CI, 1.07-2.43), acctaminophcn usc (OR =
1.41; 95% CI, 1.05-1.90), incrcascd alcohol consumption (OR = 1.24; 95% CI, 1.02-1.50), and incrcascd
agc (OR = 1.03 pcr ycar; 95% CI, 1.00-1.06).

Reference

New labeling information for warfarin (marketed as

Coumadin). http://www.fda.gov/cder/drug/infopage/
warfarin/default.htm. Accessed November 1, 2007.
The FDA has approved the Verigene Warfarin
Metabolism Nucleic Acid Test (Nanosphere, Inc.,
Northbrook, Illinois) for use in identifying patients
with variants of CTP2C9 and VKORC1. This test is not
intended to be a stand-alone tool for determining the
optimal dosage of warfarin, but is to be used together
with clinical evaluation and other tools (including INR)
to determine the best treatment for patients.
Reference

FDA clears genetic lab test for warfarin sensitivity,http://

www.fda.gov/bbs/topics/NEWS/2OOT/NEWO1701.
html. Accessed November 1, 2007.
WARFARIN

AND

DIETARY SUPPLEMENTS

In a prospective, longitudinal study of 171 adults completing a 16-week study diary, concurrent use of dietary
supplements and complementary/alternative medications (CAM) placed warfarin recipients at an increased
risk for bleeding. At least 1 bleeding event was reported
by 87 patients (51%), and 36 (21%) had >1 supratherapeutic INR value. Seventy-three patients (43%) used at

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Reference

Shalansky S, Lynd L, Richardson K, et al. Risk of

warfarin-related bleeding events and supratherapeutic
international normalized ratios associated with complementary and alternative medicine: A longitudinal analysis. Pharmacotherapy. 2007;27:1237-124Z
WARNINGS

On thc basis of postmarkcting advcrsc-cvcnt rcports,

a black box warning has been added to the product information for both glitazones (rosiglitazone
and pioglitazone). The strengthened warning advises
health care professionals to monitor patients carefully
for signs a n d / o r symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and edema)
after the initiation of therapy. Patients who develop
these symptoms and are then diagnosed with heart
failure should receive appropriate heart failure treatment, and use of the glitazone should be reconsidered.
These drugs should not be used in patients with severe
heart failure who have marked activity limitations (ie,
are comfortable only at rest or are confined to b e d /
chair). It should be emphasized that both glitazones
have been linked to the adverse CV outcome of heart
failure; hence, this adverse event appears to be class
specific.

Updates The AmericanJournal of Geriatric Pharmacotherapy

Reference

Manufacturers of some diabetes drugs to strengthen

warning on heart failure risk: Companies will include
boxed warning on drug label, http://www.fda.gov/
bbs/topics/NEWS/2 00 7/NEWO168 3.html. Accessed
November 3, 2007.
Gadolinium-based contrast agents for magnetic
resonance imaging (MRI) have been found to be associated with an increased risk for development of a rare
but serious disorder called nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal
impairment (glomerular filtration rate <30 m L / m i n
per 1.73 m 2) and those with renal impairment associated with hepatorenal syndrome or liver transplantation. The majority of cases have occurred in patients
maintained on hemodialysis. NSF is characterized by
excessive formation of connective tissue in the skin
and internal organs, leading to disability and death.
As of September 12, 2007, the FDA had received
>250 case reports of NSF occurring after administration of gadolinium-based contrast agents. 1 In cases
in which the specific agent was identified, the most
commonly implicated agents, from highest to lowest,
were gadodiamide, gadopentetate dimeglumine, and

gadovcrsetamide. In a retrospective study of 370 patients with severe renal impairment who received gadodiamide, the estimated risk for NSF was 4%. 2
It should be emphasized that the true extent of the risk
associated with any specific agent is not currently known,
nor is the risk (if any) in patients with mild or moderate
renal impairment. In at-risk patients, use of these agents
should be avoided unless the potential diagnostic information is essential and unavailable using non-contrastenhanced MRI. All patients who are to receive these contrast agents must be screened for renal impairment. The
recommended dose should not be exceeded, and, before
readministration, a sufficient period of time should be
allowed for elimination of the agent.
References

1. Information for Healthcare Professionals. Gadolinium-based

contrast agents for magnetic resonance imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK,
ProHance). http: //wvee<fda.gov/cder/drug/InfoSheets/
HCP/gcca_200705.htm. Accessed November 1, 2007.
2. Marckmann P, Skov L, Rossen K, et al. Nephrogenic
systemic fibrosis: Suspected causative role ofgadodiamide
used for contrast-enhanced magnetic resonance imaging.
J A m Soc Nephrol. 2006;17:2359-2362.

Address c o r r e s p o n d e n c e to: David R.P. Guay, PharmD, College of Pharmacy, University of Minnesota, 7-115C
Wcavcr-Densford Hall, 308 Harvard Street SE, Minneapolis, M N 55455. E-mail: guayx001@umn.edu

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