ARBs and the Impact of Worsening Renal Function in Heart Failure Patients With Preserved EF

12 Pages·2015·15.14 MB·English

FEATURE
Heart Failure
ARBs and the Impact of
Worsening Renal Function in
Heart Failure Patients With
Preserved EF
Jimena a. Blandon, md

review
Treatment of
Damman K, Perez AC, Anand IS, et al. Worsening renal function and outcome
worsening
in heart failure patients with preserved ejection fraction and the impact of
renal function
angiotensin receptor blocker treatment. J Am Coll Cardiol. 2014;64(11):1106-
in heart failure
1113.
patients with
preserved Heart failure (HF) has become a major global public health con-
ejection fraction cern, affecting about 10% of men and 60% of women by the
remains an area of age of 60 years.1 The prevalence in developing countries is ap-
controversy. proximately 2%, and the numbers increase as the population grows
older; its prevalence in the United States alone has risen overall to
approximately 5.7 million. Nearly 500,000 new cases are diagnosed
each year, causing more than 55,000 deaths annually.2
Worsening renal function (WRF) over time is associated with poor-
er outcomes in patients with acute and chronic HF. Although this
association is established in patients with reduced ejection fraction
(HFrEF), there are no data about the relationship between WRF and
outcomes in HF patients with preserved ejection fraction (HRpEF).
Controversy exists as to whether WRF is always associated with poor
outcome.
The goal of the present study by Damman and colleagues3 was to
investigate the relationship between WRF and outcomes in patients
with HFpEF, and to examine the interaction of the renin-angioten-
sin-aldosterone system (RAAS) blockade. Researchers investigated
change in estimated glomerular filtration rate (eGFR) over time, the
jump to
ommentary occurrence of WRF and its association with clinical outcomes, and
interaction with randomized treatment in patients with HFpEF who
were part of the I-PRESERVE (Irbesartan in Heart Failure with Pre-
served Ejection Fraction) trial.4 I-PRESERVE investigated both the
relationship between WRF and outcomes in patients with HFpEF and
the interaction with RAAS blockade in treatment with angiotensin
receptor blocker (ARB) medications.
Study Details
I-PRESERVE was an international, double-blind, placebo-controlled
study with results initially published in 2008. The original trial in-
cluded 4128 patients at least 60 years of age; NYHA class II, III, or
IV heart failure; and an ejection fraction of at least 45%. The patients
were randomized to receive placebo or irbesartan 300 mg/d. The
present trial enrolled 3595 patients (87% of all randomized patients)
divided into 2 groups: 1659 received irbesartan and 1707 received
placebo. Both groups had similar characteristics at admission and ran-
domization: EF >45%, elevated brain natriuretic peptide (BNP >400
pg/mL) or N-terminal prohormone of BNP (proBNP >1600 pg/mL),
and a serum creatinine (SCr) level >221 mmol/L (2.5 mg/dL).
These 2 groups were similar with regard to renal function (mean
GFR, 74-75 mL/min/1.73 m2) type 2 diabetes (3.8% in irbesartan,
3.6% in placebo group), hypertension, coronary artery disease, and
atrial fibrillation. Applied criteria for exclusion was baseline SCr >2.5
mg/dL, renal impairment (eGFR ≤40 mL/min/1.73 m2), hyperkalemia
>5 mEq/L, and comorbid conditions that signified expected survival
of less than 3 years.
The treatments and stages of heart failure were similar in the 2
groups. The patients were randomized to receive either irbesartan
starting at 75 mg/d, with the dose being doubled to 150 mg/d after
1 to 2 weeks and increased up to 300 mg/d after an additional 1 to
2 weeks as tolerated, or placebo. The patients were followed every 2
weeks for 8 weeks, and then at 6, 18, and 30 months.
The primary outcome was defined as the first occurrence of cardio-
vascular (CV) death or HF hospitalization (eg, worsening EF, unstable
angina, myocardial infarction, ventricular arrhythmia, atrial arrhyth-
mia, or stroke). Secondary outcomes included all-cause mortality, HF
hospitalization, the combined end point of all-cause mortality, or HF
hospitalization.
During a median follow-up of 46 months, the primary outcome
(CV death or HF hospitalization) occurred in 895 patients (24.9%). A
total of 85 patients (37%) with WRF (HR, 1.97; 95% CI, 1.41-2.17;
P = .001) and 810 patients (24%) without WRF reached the com-
bined outcome. In univariate analyses, WRF was consistently associ-
ated with an increased risk of developing the primary outcome and
was related to poor clinical results. Patients affected by renal failure in
the irbesartan group were more likely to reach the primary outcome.
The secondary end points were reached in a similar magnitude in pa-
tients with WRF, but after multivariate adjustment, the interaction be-
tween treatment allocation and WRF on the effect of CV death or HF
hospitalization was no longer significant—although it remained so for
all-cause mortality.
Notably, drug discontinuation rates were very low, with no differ-
ence observed between the placebo and irbesartan groups. Patients
in the irbesartan group who developed WRF exhibited a significantly
greater reduction in mean arterial blood pressure (MAP) at 8 weeks
compared with those who did not experience WRF. In a mixed-effect
linear model, changes in MAP showed a significant positive associa-
tion with changes in eGFR over time, and there was a significant mul-
tivariate adjusted interaction between irbesartan treatment allocation,
changes in MAP, and changes in eGFR over time (P = .004).
FEATURE
Heart Failure
ommentary
Are the findings
solid enough to
draw conclusions? This study reflects the fact that WRF was associated with a
bad clinical outcome in CV mortality and HF hospitaliza-
tion. This primary end point was detected in 37% of patients
with WRF versus only 24% of patients without WRF (P <.001).
Univariate analysis showed that patients with HFpEF who were
taking irbesartan had twice the risk of WRF and reaching the pri-
mary end point. Using a multivariate analysis, WRF was associated
with the primary outcome in the overall population and the irbe-
sartan group, but not in the placebo group.
WRF is a well-known and expected manifestation of RAAS sys-
tem inhibition, and has been thought to be a marker of successful
suppression of highly elevated and deleterious renin and aldoste-
rone levels.5 WRF occurs in both systolic and diastolic heart failure
and with both angiotensin-converting enzyme (ACE) inhibitor and
ARB treatment. The exact mechanism involves renal perfusion and
decreases in systemic blood pressure, tone in efferent arteriolar va-
soconstriction, glomerular perfusion pressure, and filtration.
The present study found a 6% to 14% incidence of WRF de-
pending on definition criteria, which is similar to the incidence of
WRF observed in other studies using other RAAS system block-
ers. However, multivariate adjustment failed to show a significant
relationship between WRF and allocation to irbesartan or placebo
with the primary outcome, although it was positive for all-cause
mortality.
In retrospective analysis of previous clinical trials using ACE in-
hibition in patients with HFrEF, the occurrence of WRF has been
associated with a better prognosis, as shown in the SOLVD study,
where patients in the enalapril group who developed WRF had a
better prognosis than those with WRF in the placebo group.5 In the
SAVE study, patients treated with captopril who developed WRF
had better outcomes than those developing WRF in the placebo
group.6 Similar results were seen with the use of eplerenone, a min-
eralocorticoid receptor antagonist, and with valsartan, an ARB
agent.7,8
In contrast with the findings on the Val-HeFT study, which used
valsartan in patients with HFrEF, the initiation of irbesartan in this
population was associated with a higher incidence of critical events
rate-independent of other risk factors. The Val-HeFT investigators
theorized that irbesartan did not have an overall benefit and thus
could not counterbalance the negative effects on renal function. In
the present study by Damman et al, the patients in the irbesartan
group may have had more venous congestion and water and salt
retention given the fact that they had higher levels of NT-proBNP.
Other limitations of this study are important to discuss, includ-
ing that it is a retrospective study. In addition, patients taking ir-
besartan did not have any overall improvement, and only a small
subset of patients (229 of 3595) developed WRF, making it difficult
to make solid conclusions. It is thus possible that the findings re-
flect only serendipity.
In conclusion, randomized controlled trials that assess the rela-
tionship between WRF and hard CV events (eg, death, hospitaliza-
tions, worsening HF) in patients with HFpEF treated with RAAS
inhibitors are much needed before it will be possible to conclude
that ARB agents, such as irbesartan, are not effective or are unde-
sirable in treating this group of patients.
References
1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke sta-
tistics—2012 update: a report from the American Heart Association. Cir-
culation. 2012;125:2-220.
2. Kochanek KD, Xu JQ, Murphy SL, Miniño AM, Kung HC. Deaths: final
data for 2009. National Vital Statistics Reports. 2011;60(3). CDC website.
www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_03.pdf.
3. Damman K, Perez AC, Anand IS, et al. Worsening renal function and
outcome in heart failure patients with preserved ejection fraction and
the impact of angiotensin receptor blocker treatment. J Am Coll Cardiol.
2014;64:1106-1113.
4. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients
with heart failure and preserved ejection fraction. N Engl J Med.
2008;359:2456-2467.
5. Testani JM, Cappola TP, McCauley BD, et al. Impact of worsening
renal function during the treatment of decompensated heart failure on
changes in renal function during subsequent hospitalization. Am Heart J.
2011;161:944-949.
6. Jose P, Skali H, Anavekar N, et al. Increase in creatinine and cardiovas-
cular risk in patients with systolic dysfunction after myocardial infarction.
J Am Soc Nephrol. 2006;17:2886-2891.
7. Rossignol P, Cleland JG, Bhandari S, et al. Determinants and conse-
quences of renal function variations with aldosterone blocker therapy in
heart failure patients after myocardial infarction: insights from the Eplere-
none Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival
Study. Circulation. 2012;125:271-279.
8. Lesogor A, Cohn JN, Latini R, et al. Interaction between baseline and
early worsening of renal function and efficacy of renin-angiotensin-aldo-
sterone system blockade in patients with heart failure: insights from the
Val-HeFT study. Eur J Heart Failure. 2013;15:1236-1244
About the Author
Jimena a. Blandon, md, is a fellow in nephrology at Cleveland Clin-
ic Florida in Weston, Florida. Dr Blandon completed her residency
in internal medicine at the Paul Foster School of Medicine at Texas
Tech University Health Sciences Center in El Paso, Texas. She re-
ceived her MD at Universidad del Valle in Cali, Colombia.
FEATURE
Smoking Cessation
Comparing Varenicline With and
Without Nicotine Replacement
Therapy for Smoking Cessation
Saurav Chatterjee, MD

review
Does
Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined
combined
with nicotine replacement therapy vs varenicline alone for smoking cessation:
varenicline
a randomized clinical trial. JAMA. 2014;312:155-161.
with nicotine
replacement
transdermal Smoking cessation remains a public health priority.While various
patches work behavioral and pharmacologic agents have proven to be effec-
better than tive and safe for continued smoking cessation, a combination of
varenicline alone? varenicline and nicotine replacement (NRT) with transdermal patches
has not been shown definitively to be more efficacious than vareni-
cline alone. In the framework of a randomized clinical trial (RCT),
the present study evaluates whether a combination of varenicline with
NRT improved smoking cessation rates and abstinence duration com-
pared with varenicline alone.
Study Design
This study by Koegelenberg et al was a randomized, double-blind-
ed, placebo-controlled clinical trial conducted at 7 centers in South
Africa (in Cape Town, Johannesburg, and Durban), with a 12-week
treatment period and a 12-week follow-up, from April 2011 to Oc-
tober 2012.1 A total of 446 smokers (171 men; mean age, 46.3 years)
without significant comorbidities were randomized in a 1:1 ratio; 435
were included in the efficacy and safety analyses. Participants were
randomized to either active 15-mg nicotine patches or placebo patch
jump to
ommentary treatment for 16 hours/day, which began 2 weeks before a target quit
date (TQD) and continued for an additional 12 weeks. Varenicline
(0.5 mg once daily for 3 days, titrated to 0.5 mg twice daily for days
4 to 7 and then to the maintenance dose of 1 mg twice daily through
week 12) was begun 1 week prior to the TQD, continued for an addi-
tional 12 weeks, and tapered off during week 13. Tobacco abstinence
was confirmed by measuring exhaled carbon monoxide using the Mi-
cro IV Smokerlyzer (Bedfont Scientific, Kent, England) at the TQD
and at intervals thereafter for up to 24 weeks.
The primary end point was the 4-week exhaled carbon monoxide-
confirmed continuous abstinence rate for weeks 9 through 12 of treat-
ment. (The rate was the proportion of participants able to maintain
complete abstinence from smoking for the last 4 weeks of treatment,
as assessed using separate per protocol and multiple imputation anal-
ysis.) Secondary end points included point prevalence abstinence at
6 months, continuous abstinence rate from weeks 9 through 24, and
adverse events.
The combination treatment was associated with a higher continu-
ous abstinence rate at 12 weeks (55.4% vs 40.9%; odds ratio [OR],
1.85; 95% confidence interval [CI], 1.19-2.89; P = .007) and at 24
weeks (49.0% vs 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004),
and point prevalence abstinence rate at 6 months (65.1% vs 46.7%;
OR, 2.13; 95% CI, 1.32-3.43; P = .002).
The mean weight gain in those who completed 6 months of follow-
up was 3.0 kg (95% CI, 2.3-3.8 kg) in the active and 2.2 kg (95% CI,
1.7-2.8 kg) in the placebo NRT groups, respectively (P = .09). In the
combination treatment group, there was a numerically greater inci-
dence of nausea, sleep disturbance, skin reactions, constipation, and
depression, with only skin reactions reaching statistical significance
(14.4% vs 7.8%; P = .03). The varenicline-alone group experienced
more abnormal dreams and headaches.
The investigators concluded that varenicline, in combination with
NRT, was more effective than varenicline alone at achieving tobacco
abstinence at 12 weeks (end of treatment) and at 6 months. Further
studies are needed to assess the long-term efficacy and safety of the
combination.
FEATURE
Smoking Cessation
ommentary
Enhancing
the efficacy of
varenicline with Many anti-addiction modalities have been shown to be su-
nicotine patches
perior to placebo in achieving successful abstinence for
chronic smokers.2 In a prior meta-analysis,3 varenicline
was shown to be superior to both NRT (OR, 1.57; 95% CI, 1.29-
1.91) and bupropion (OR, 1.59; 95% CI, 1.29-1.96), but not to an
NRT combination (OR, 1.06; 95% CI, 0.75-1.48). Combination
therapy with different drugs may provide a therapeutic advantage
by increasing the serum nicotine concentrations and by comple-
mentary effects obtained from 2 different mechanisms of action.4,5
The physiologic basis proposed for the synergistic action appears
to be that varenicline may not fully saturate the nicotinic receptors,
and incompletely saturated receptors may lead to only partial at-
tenuation of nicotine cravings. If supplemental NRT is used, more
receptor saturation may potentially be achieved, thereby reducing
the urge to smoke.
Recently, a randomized controlled trial6 observed that the addi-
tion of nicotine patches to varenicline among smokers who smoked
10 or more cigarettes per day did not increase the efficacy of var-
enicline as a monotherapy. A recent randomized Spanish trial con-
cluded that in those who smoked 20 or more cigarettes per day for
6 months prior, the combination of varenicline with the nicotine
patch did not improve abstinence rates at 12 weeks and 24 weeks
compared with varenicline alone when all smokers were analyzed
independent of consumption level.7 In contrast, the study under
current consideration showed that the efficacy of varenicline was
enhanced by the addition of nicotine patches.1
Reported randomized studies that have measured the effective-
ness of combining varenicline with nicotine patches have had in-
congruent reports.1,7 A study by Hajek et al,6 which used the same
method as the present trial with medication started as per label-
ing, found no effect of the combination treatment at 3 months;
in the current study, patch use was started 2 weeks prior to target
quit date. Thus, a possibility remains that the results could reflect
the effects of “nicotine preloading” rather than those of medication
combination.1 The 2 studies that did not show significant benefit of
combination therapy included smokers of 20 cigarettes or more,6,7
in contrast to this study, in which the participants smoked 10 or
more cigarettes. Finally, another potential limitation is the possibili-
ty for bias with nonpharmacologic interventions, such as simultane-
ous behavioral interventions that some subjects may have used.
References
1. Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline
combined with nicotine replacement therapy vs varenicline alone for
smoking cessation: a randomized clinical trial. JAMA. 2014;312:155-161.
2. Mills EJ, Wu P, Lockhart I, Thorlund K, Puhan M, Ebbert JO. Com-
parisons of high-dose and combination nicotine replacement therapy, va-
renicline, and bupropion for smoking cessation: a systematic review and
multiple treatment meta-analysis. Ann Med. 2012;44:588-597.
3. Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interven-
tions for smoking cessation: an overview and network meta-analysis. Co-
chrane Database Syst Rev. 2013;5:CD009329.
4. Shah SD, Wilken LA, Winkler SR, Lin SJ. Systematic review and meta-
analysis of combination therapy for smoking cessation. J Am Pharm Assoc.
2008;48:659-665.
5. Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel
selective nicotinic acetylcholine receptor partial agonist, varenicline, for
smoking cessation. Arch Intern Med. 2006;166:1571-1577.
6. Hajek P, Smith KM, Dhanji AR, McRobbie H. Is a combination of va-
renicline and nicotine patch more effective in helping smokers quit than
varenicline alone? A randomised controlled trial. BMC Med. 2013;11:140.
7. Ramon JM, Morchon S, Baena A, Masuet-Aumatell C. Combining var-
enicline and nicotine patches: a randomized controlled trial study in smok-
ing cessation. BMC Med. 2014;12(1):172.
About the Author
Saurav Chatterjee, MD, is clinical and research fellow in cardiology
at the St Luke’s-Roosevelt Hospital of the Columbia University of
Physicians and Surgeons. He graduated from Calcutta National
Medical College with honors and was a resident in cardiology in
Mercy Hospital, Kolkata, India, as well as trial coordinator of the
CRESCENDO trial in Kolkata, India. He recently completed his
residency in internal medicine at Maimonides Medical Center in
Brooklyn, NY, and was Clinical and Research Fellow in Preventive
Cardiology and Outcomes Research at Brown University and Provi-
dence VAMC in Providence, Rhode Island. Dr Chatterjee is the re-
cipient of the 2012 Young Investigator Award for Health Outcomes
and Population Genetics at the Annual Scientific Sessions of the
American College of Cardiology 2012 in Chicago, and also the
2011 American Association of Cardiologists of Indian Origin (AA-
CIO) Young Investigator Award for Interventional Cardiology and
Electrophysiology.
FEATURE
Preventive Cardiology
Medication-Free Strategies Can
Prevent Coronary Heart Disease
Harry E. Davis ii, MD, MaCP

review
This study
Akesson A, Larsson SC, Discacciati A, Wolk A. Low-risk diet and lifestyle habits
examined
in the primary prevention of myocardial infarction in men: a population-based
the benefit of a
prospective cohort study. J Am Coll Cardiol. 2014;64:1299-1306.
combined healthy
diet and lifestyle
Drug therapy is recognized as an effective way to lower lipids
on the incidence
and control hypertension, and for its effect on reducing the in-
of myocardial
cidence of myocardial infarction (MI).1,2 However, the impact
infarction in a
cohort of healthy of personal habits, such as eating, drinking, smoking, and exercise, on
Swedish men. the incidence of coronary heart disease (CHD) without reliance on
prescription medications and their potential side effects may be less
well established.
Study Details
Akesson et al looked at this question by examining a large, popula-
tion-based prospective cohort of healthy Swedish men to determine
if specific preventive efforts could have a beneficial effect on the inci-
dence of MI.3 Their methodology called for sending questionnaires to
all males aged 45 to 79 years residing in 2 counties in central Sweden.
With a response rate of 49%, they then excluded men with a history
of cancer, ischemic heart disease, stroke, hypertension, high choles-
terol, diabetes, and those with extremes of caloric intake. This left
20,721 men for analysis. They followed this cohort until the date of
the first event of MI, death, or end of the follow-up period.
jump to Diet was assessed using a self-administered food frequency ques-
ommentary
tionnaire (FFQ) on 96 commonly eaten foods. A healthy or low-risk
diet was defined as including foods with a beneficial effect on cardio-
vascular health, such as fruits, vegetables, legumes, nuts, reduced-fat
dairy products, whole grains, and fish. The investigators assigned a
Recommended Food Score of 1 for more than 1 serving per week
of any of 3 reduced-fat dairy products, crisp bread, and whole grain
bread, and for consuming the remaining food items at least 1 to 3
times per month, for a maximum of 25 points. They considered those
who scored in the highest quintile (23 to 25) as having a very healthy,
low-risk diet. This division of the results was due to the finding that
only the top quintile was associated with a statistically significant de-
creased risk of MI. Conversely, a high-risk diet was identified using a
non-Recommended Food Score based on 21 food items including red
and processed meat, fried potatoes, solid fats, full-fat cheese, white
bread, refined cereals, and various sweet foods. This score was then
used to adjust risk.
Lifestyle was examined using questionnaire data regarding alcohol
consumption, smoking, physical activity, and abdominal adiposity. Al-
cohol consumption of 10 to 30 g daily was considered low risk. Study
subjects who never smoked and those who had stopped smoking ≥20
years ago were classified as nonsmokers. Physical activity was consid-
ered low risk in men who walked or cycled for at least 40 minutes per
day and exercised at least 1 hour per week. A waist circumference less
than 95 cm was considered low risk. The investigators then analyzed
the data to estimate the percentage of MI cases that could potentially
be prevented if men adhered to the low-risk practices.
Baseline characteristics of the cohort showed men with a low-risk
diet were more likely to have a higher level of education, and to not
smoke, and were less likely to live alone. During a mean of 11 years
of follow- up, 1361 cases of primary MI were reported in the cohort
using the Swedish National Inpatient and Cause of Death registers.
Compared with men in the high-risk group, each lifestyle factor was
independently associated with an inverse risk of coronary events in
the low-risk group. A risk reduction of 18% was seen for the healthy
diet, 11% for moderate alcohol consumption, 36% for no smoking,
3% for being physically active, and 12% for having a low abdominal
circumference.
Further analysis of the data revealed that 8.7% of the men had
combined a low-risk diet with moderate alcohol consumption. This
group consumed a daily mean of 5 servings of vegetables and fruits
and 4 servings of whole grains, and a weekly consumption of 2.2 serv-
ings of fish. Their combined low-risk behavior was associated with a
35% reduction in the risk of MI.
Finally, the comprehensive low-risk profile that included all 5 low-
risk factors was associated with an 86% lower risk of MI compared
with the high-risk group with no low-risk factors. The absolute rate
difference between men having no low-risk factors and those having
all 5 low-risk factors was 848 cases per 100,000 person-years. Un-
fortunately, this low-risk profile was fulfilled by only 1% of the study
population.
Based on their data analysis, the authors estimated that 79% of
the burden of disease in this group of healthy men without hyperten-
sion, high cholesterol, or diabetes could be reduced by adherence to a
combination of the low-risk diet, moderate alcohol consumption, and
the 3 low-risk behaviors. Thus, combining a healthy diet, moderate
alcohol consumption, no smoking, being physically active, and main-
taining a healthy weight could potentially prevent 4 of 5 MIs in the
study population.
FEATURE
Preventive Cardiology
ommentary
A healthy diet
and lifestyle and
the potential for Akesson et al provide impressive evidence for a lowered risk
a greatly reduced
of CHD with a low-risk lifestyle in a specific population of
CHD risk
Swedish males. Based on their analysis of this data, they
suggest that the combination of low-risk behaviors that include a
healthy diet, moderated alcohol consumption, no smoking, being
physically active, and maintaining a healthy weight can prevent a
majority of MI events in men.
As they discuss, the potential contribution of a low-risk lifestyle
to the reduction of the burden of disease is great. The logical con-
sequence of this study is their call for the development of “popu-
lation-based strategies to promote healthy behaviors that can be
introduced early in life and maintained throughout the life span.”
The idea that diet and lifestyle may be important factors affect-
ing health and well-being is not new. As was pointed out in a previ-
ous review,4 the Human Population Laboratory of the California
State Department of Health Services in Berkeley, California, initi-
ated a study of common health practices and their potential for
a positive effect on health in 1965.5 Later referred to as the “Al-
ameda 7,” they found 7 health habits to be associated with physi-
cal health status and mortality. These habits were: having never
smoked, drinking fewer than 2 drinks at one sitting, sleeping 7 to 8
hours a night, exercising, maintaining a desirable weight, avoiding
snacks, and eating breakfast regularly. An increased risk of death
was associated with being male, smoking, having little physical
activity, being overweight or underweight, and not regularly eat-
ing breakfast.6 More recently, Lopez-Garcia et al7 looked at men
and women with cardiovascular disease and found adherence to
a Mediterranean-style dietary pattern was associated with lower
all-cause mortality. Simply increasing the daily servings of fruit or
green leafy vegetables has been shown to be associated with a sig-
nificantly reduced risk of type 2 diabetes.8
The study by Akesson et al has again confirmed the likelihood
that diet and lifestyle are very important. It contributes to the
growing literature that supports the reduction of morbidity and
mortality through adopting healthy dietary and lifestyle patterns.
Their call for programs targeting efforts to increase adherence to
low-risk behaviors is compelling; however, the reality that only 1%
of their study population actually attained optimal lifestyle charac-
teristics cannot be overlooked. Similarly, Go et al9 found that less
than 1% of Americans met at least 4 of 5 healthy dietary goals in
2009 to 2010.
In an era when physician effectiveness may be based on patient
outcomes,10 physicians must pursue the development of patient be-
havior that increases the likelihood that patients will make healthi-
er choices. This may well be an enormous challenge. As was so well
noted many centuries ago, “The gate is narrow and the road is hard
that leads to life, and there are few who find it.”11
References
1. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholester-
ol-lowering treatment: prospective meta-analysis of data from 90,056 par-
ticipants in 14 randomised trials of statins. Lancet. 2005;366:1267-1278.
2. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in
the prevention of cardiovascular disease: meta-analysis of 147 randomised
trials in the context of expectations from prospective epidemiological stud-
ies. BMJ. 2009;338:1665
3. Akesson A, Larsson SC, Discacciati A, Wolk A. Low-risk diet and
lifestyle habits in the primary prevention of myocardial infarction in
men: a population-based prospective cohort study. J Am Coll Cardiol.
2014;64:1299-1306.
4. Davis HE. Is there something to be said for eating breakfast daily? Car-
diology Rev. 2013;29. HCPLive website. www.hcplive.com/publications/
cardiology-review-online/2013/October2013/Is-There-Something-to-Be-
Said-for-Eating-Breakfast-Daily.
5. Belloc NB, Breslow L. Relationship of physical health status and health
practices. Prev Med. 1972;1:409-421.
6. Kaplan GA, Seeman TE, et al. Mortality among the elderly in the Alam-
eda County study: behavioral and demographic risk factors. Am J Public
Health. 1987;77:307-312.
7. Lopez-Garcia E, Rodriguez-Artalejo F, Li TY, et al. The Mediterranean-
style dietary pattern and mortality among men and women with cardiovas-
cular disease. Am J Clin Nutr. 2014;99:172-180.
8. Li M, Fan Y, Zhang X, et al. Fruit and vegetable intake and risk of type 2
diabetes mellitus: meta-analysis of prospective cohort studies. BMJ Open.
2014;4:e005497.
9. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart dis-
ease and stroke statistics-2014 update: a report from the American Heart
Association. Circulation. 2014;129:399-410.
10. Hershberger PJ, Bricker DA. Who determines physician effectiveness?
JAMA. Published online October 13, 2014. doi:10.1001/jama.2014.13304.
11. Matthew 7:14. In: Metzger BM, Murphy RE, eds. The New Oxford
Annotated Bible with the Apocryphal/Deuterocanonical Books, New Re-
vised Standard Version. NY: Oxford University Press; 1994.
About the Author
Harry E. Davis ii, MD, MaCP, is Associate Professor of Medicine and
Vice Chair for Education in the Department of Internal Medicine,
Texas Tech University Medical Sciences Center, El Paso, Texas. Dr
Davis received his medical degree from West Virginia University in
Morgantown, West Virginia, and did his internal medicine residen-
cy at Philadelphia General Hospital in Philadelphia, Pennsylvania,
and Letterman Army Medical Center in San Francisco, California.
He has practiced medicine with the US Army in many capacities,
including Chief of Emergency Medicine in Fort Lewis, Washington,
Division Surgeon in the 1st Infantry Division, Fort Riley, Kansas, and
as Commander of the Field Hospital/Chief Medical Officer with the
UN Forces in Port-au-Prince, Haiti. Dr Davis has received numerous
honors and awards for service and teaching.
FEATURE
Atrial Fibrillation
Increased Mortality Associated
With Digoxin in AF Patients
KazuhiKo Kido, Pharmd, and
Tracy E. macaulay, Pharmd, aacc, BcPS-aQ cardiology

review
Prior to this
Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality asso-
study, no
ciated with digoxin in contemporary patients with atrial fibrillation. Findings
randomized
from the TREAT-AF Study. J Am Coll Cardiol. 2014;64:660-668.
controlled
clinical trials had
Although digoxin has a very long clinical history, no random-
evaluated digoxin
ized controlled trial (RCT) has evaluated the use of digoxin
for AF.
for atrial fibrillation (AF). Therefore, the evidence for its use
in AF is based on post hoc analyses of RCTs or on findings from ob-
servational studies. Several studies have shown the association of
digoxin use with increased mortality rates.1,2 However, other studies
have reported the opposite conclusions,3,4 and it remains controversial
whether digoxin use is associated with increased mortality in patients
with AF.
Study Details
Turakhia and colleagues recently published a report in the Journal
of the American College of Cardiology of their evaluation of digoxin
use in patients with newly diagnosed, nonvalvular AF and its associa-
tion with mortality.5 The Retrospective Evaluation and Assessment of
Therapies in AF (TREAT-AF) was a retrospective cohort study from
the Veterans Affairs (VA) health care system outpatient database be-
tween VA fiscal years 2004 and 2008. Key inclusion criteria were
a primary or secondary diagnosis of AF by ICD-9 codes 427.31 or
427.32 in a VA inpatient or outpatient encounter, a second confir-
matory diagnosis 30 to 365 days after the initial diagnosis, and an
outpatient follow-up visit in the clinic 90 days after the initial diag-
nosis. Main exclusion criteria included prior AF diagnosis, history of
valve diseases, thyroid disease, kidney transplant, or cardiac surgery
within the previous 30 days. The primary outcome was time to death,
beginning from 90 days after index AF diagnosis. Cox multivariate
regression analysis was performed to adjust for the effect of variables
jump to
in both the full study population and in a propensity-matched cohort.
ommentary
The full study cohort included 122,465 patients from the VA health
care system centralized data sets. The mean age of the patients was
72.1 years; 1.6% were women, and 36.8% had impaired renal func-
tion (estimated glomerular filtration rate <60 mL/min/1.73 m2 or on
dialysis). Baseline characteristics between digoxin recipients and non-
recipients were similar in age and race, but the percentage of patients
with heart failure (HF) or who used beta-blockers, angiotensin recep-
tor blockers, antiplatelet therapy, diuretics, and warfarin was signifi-
cantly higher in the digoxin recipient group. Of note, ejection fraction
was not included in the evaluation. The propensity-matched cohort
demonstrated comparable baseline characteristics between digoxin re-
cipients and nonrecipient groups (n = 26,703 in each group), with no
statistically significant differences in characteristics.
Digoxin use was associated with an increased mortality rate in the
unadjusted full cohort (hazard ratio [HR], 1.37; 95% confidence in-
terval [CI], 1.33-1.40; P <.001). The association persisted but the de-
gree of this association was attenuated in multivariate Cox regression
analysis (HR, 1.26; 95% CI, 1.23-1.29; P <.001) and after propensity
matching (HR, 1.21; 95% CI, 1.17-1.25; P <.001). The association
was consistent across subgroups based on drug adherence, clinical co-
morbidities, concomitant therapy, and kidney function. The risk may
be increased in patients with prior myocardial infarction (MI) based
on subgroup analysis in both the full cohort (HR, 1.49; 95% CI, 1.34-
1.67; P value for interaction, .002) and the propensity-matched co-
hort (HR, 1.45; 95% CI, 1.26-1.66; P value for interaction, .077).
FEATURE
Atrial Fibrillation
ommentary
A study with many
strengths
Currently, few other studies have evaluated the effect of di-
goxin use on mortality rate in AF. One of the published pro-
spective studies is the Stockholm cohort study, with 2824
patients followed for approximately 4.6 years prospectively.2 Pro-
pensity score matching and Cox multivariate regression analysis
were utilized. Investigators found that digoxin use was associated
with increased mortality (HR, 1.94; 95% CI, 1.71-2.20; P <.001),
but the association was no longer observed after adjusting for base-
line differences (HR, 1.05; 95% CI, 0.92-1.20).
Two post-hoc analyzes of the Atrial Fibrillation Follow-up Inves-
tigation of Rhythm Management (AFFIRM) trial have evaluated
the relationship between digoxin therapy and mortality in patients
with AF, with different outcomes.3,4 The first group assessed the
association between digoxin and mortality using multivariate Cox
proportional hazards models.3 They found that digoxin was associ-
ated with the increased all-cause mortality rate (HR, 1.35; 95% CI,
1.06-1.71; P = .016). Remarkably, it also showed that there was no
significant digoxin-gender interaction for all-cause mortality, and
interactions existed regardless of HF status. The second group em-
ployed a different trial design to the same AFFIRM cohort, using
propensity score matching, and found no negative association be-
tween digoxin use and mortality (HR, 1.06; 95% CI, 0.83-1.37;
P = .64).4 Conflicting findings in these evaluations still offer little
resolution to the safety of digoxin use in patients with AF.
This large retrospective cohort study has remarkable strengths.
First, the database-based cohort study included the largest AF co-
hort, which allows this study to conduct more robust subgroup
analysis based on age, drug adherence, kidney function, past medi-
cal histories of MI or HF, or concomitant therapy with warfarin,
beta-blockers, and amiodarone, without any concern for type 2
error. Also, multivariate logistic analysis was conducted in the pro-
pensity-matched cohort because of the large sample size. Second,
the VA database in the TREAT-AF trial may be more representa-
tive of current US practice than the other data sources were, and
may be more applicable to current medicine practice. For example,
the AFFIRM trial6 was published in 2002 and the TREAT-AF trial
collected data from 2003 to 2008. The outcomes of earlier studies
could have been affected by not being able to use more contempo-
rary treatments for HF, CAD, and stroke prevention, thus resulting
in lower external validity. 
Several limitations do exist. The most notable is that the TREAT-
AF study is not randomized, merely observational. Therefore, find-
ings from this study should be applied with caution. Also, some
other features of this study design limit generalizability. First, this
cohort mainly included male veterans, which makes it difficult to
apply findings to women. The Digitalis Investigation Group trial
showed the effect of sex on mortality in patients with HF, but the
relationship between digoxin use and outcomes was more signifi-
cant in the subgroup of women.7 In addition, the cohort only in-
cluded newly diagnosed AF patients; the AFFIRM trial population
was more elderly, asymptomatic, or marginally symptomatic. More
important, this cohort study was not able to include assessments
of New York Heart Association functional class or measures of
left ventricular ejection fraction, whereas differences in these vari-
ables could have affected the results. However, the AFFIRM trial
post-hoc study by Whitbeck et al3 showed that digoxin use was
associated with a significantly increased mortality in AF patients
regardless of the presence or absence of HF.
It remains a matter of controversy whether patients maintained
on digoxin should be stopped completely based only on study re-
sults from this observational study. However, at the least, the use
of digoxin should be strictly evaluated and its initiation selected
with care in AF patients. Until further evaluation, digoxin should
be reserved for patients who have symptomatic hypotension and/or
HF with reduced ejection fraction when other rate-control agents
cannot be safely initiated.
References
1. Hallberg P, Lindback J, Lindahl B, et al. Digoxin and mortality in
atrial fibrillation: a prospective cohort study. Eur J Clin Pharmacol.
2007;63:959-971.
2. Friberg L, Hammar N, Rosenqvist M. Digoxin in atrial fibrillation: re-
port from the Stockholm cohort study of atrial fibrillation (SCAF). Heart.
2010;96:275-280.
3. Whitbeck MG, Charnigo RJ, Khairy P. et al. Increased mortality among
patients taking digoxin—analysis from AFFIRM study. Eur Heart J.
2013;34:1481-1488.
4. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, et al. Lack of evi-
dence of increased mortality among patients with atrial fibrillation taking
digoxin: findings from post-hoc propensity-matched analysis of the AF-
FIRM trial. Eur Heart J. 2013;34:1489-1497.
5. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality
associated with digoxin in contemporary patients with atrial fibrillation. J
Am Coll Cardiol. 2014;64:660-668.
6. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control
and rhythm control in patients with atrial fibrillation. N Engl J Med.
2002;347:1825-1833.
7. The Digitalis Investigation Group. The effect of digoxin on mortality
and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-
533.
About the Author
KazuhiKo Kido, Pharmd, is a PGY2 cardiology pharmacy resident
at the University of Kentucky HealthCare, Lexington, Kentucky.
He was assisted in the writing of this article by Tracy E. macaulay,
Pharmd, aacc, BcPS-aQ cardiology, clinical pharmacy specialist-
cardiology, PGY2 residency program director-cardiology, and ad-
junct assistant professor at University of Kentucky HealthCare in the
Department of Pharmacy Services and Division of Cardiovascular
Medicine, Lexington, Kentucky.
FEATURE
Interventional Cardiology
Drug-Eluting Versus Bare-Metal
Stents in Saphenous Vein Bypass
Graft PCI
Glenn n. levine, MD, FAHA, FACC

review
A study that
Aggarwal V, Stanislawski MA, Maddox TM, et al. Safety and effectiveness of
adds to our
drug-eluting versus bare-metal stents in saphenous vein bypass graft percuta-
understanding
neous coronary intervention. J Am Coll Cardiol 2014;64:1825-1836.
of SVG-PCI.
It is generally accepted that drug-eluting stents (DES) decrease the
risk of restenosis in native coronary arteries compared with bare
metal stents (BMS). However, the overall safety and benefit of DES
implantation, including long-term benefits, in saphenous vein bypass
grafts (SVGs) remains the subject, at least to some extent, of contin-
ued evaluation. This issue is of great clinical importance because by
10 years after bypass surgery, half of SVGs are occluded, and of those
still patent, half are diseased.1,2 A recent report3 by Aggarwal and
colleagues adds to our understanding of who is being treated with
DES for SVG percutaneous coronary intervention (PCI) and what the
short- and long-term outcomes of their use are compared with BMS
for SVG-PCI.
Study Details
In this study, Aggarwal and colleagues sought to utilize data from
the Veterans Affairs (VA) CART Program to assess patient and le-
sion characteristics and the acute and long-term outcomes of patients
treated with DES or BMS during SVG-PCI. The VA-CART program
is a national database of all 63 VA medical centers that perform PCI.
The data are linked with VA electronic health records, allowing for
linkage to longitudinal outcome data, as well as fee-based data for
non-VA care. Data elements in VA-CART are standardized and based
on the American College of Cardiology (ACC) National Cardiovascu-
lar Data Registry (NCDR) for catheterization-PCI.
This retrospective study used data from all patients undergoing
their first procedure of a SVG-PCI from October 1, 2007, through
September 30, 2011. Patients who had undergone previous SVG-PCI,
who received both DES and BMS, or had missing key data were ex-
cluded from analysis. Overall, approximately two-thirds of treated
patients received DES. Of that group, 34% received first-generation
DES (defined as either paclitaxel-eluting or sirolimus-eluting stents)
and 64% received second-generation DES (defined as either everolim-
us-eluting or zotarolimus-eluting stents). Approximately 56% of pa-
tients had non-ST-elevation acute coronary syndromes (NSTE-ACS),
5% had ST-segment elevation myocardial infarction (STEMI), and
26% had stable angina or chest pain (the remainder of the procedures
jump to
were for other or unclear indications). Outcomes were analyzed using
ommentary
propensity-matched cohorts using Cox proportional hazards regres-
sion models.
The use of DES increased each year of the study, from 50% the first
year to 69% during the last year. DES tended to be used more com-
monly for anastomotic lesions; BMS tended to be used more common-
ly in treating lesions in the “body” of the SVG. DES tended to be used
more commonly in SVG to a diagonal branch, whereas BMS tended
to be used more commonly in SVG to the right coronary artery. Use of
embolic protection devices was similar with DES and BMS (a some-
what disappointing 38%-39%). In general, procedural complication
rates were low and comparable between those treated with DES and
those treated with BMS. For the overall (nonpropensity-matched)
study population, the incidence of procedural complication was 2.3%
in DES-treated patients and 2.8% in BMS-treated patients (P = .54).
For the propensity-matched cohort, no procedural complication was
reported in 93.7% of DES-treated patients and in 93.9% of BMS-
treated patients (P = .54). Postprocedure thrombolysis in myocardial
infarction (TIMI) flow grade 3 was reported in 88.6% of DES-treated
patients and in 89.2% of BMS-treated patients.
Over a mean follow-up of 30 months, there was no significant dif-
ference in MI rates between those receiving a DES and those receiving
a BMS. The adjusted hazard ratio (HR) for any DES versus BMS was
.94 (confidence interval [CI}, .71-1.24), the adjusted HR for first-gen-
eration DES versus BMS was .88 (CI, .62-1.23), the adjusted HR for
second-generation DES versus BMS was 1.00 (CI, .72-1.36), and the
adjusted HR for second-generation DES versus first-generation DES
was 1.13 (CI, .81-1.58).
In the propensity-matched cohort, over a mean follow-up of 33
months, patients receiving a DES were less likely to experience mor-
tality than those receiving a BMS (HR, .72; CI, .57-.89). This finding
did not change after further adjusting for lesion location within the
graft and target native vessel. There was no statistically significant
difference in mortality between those treated with a first- or second-
generation DES.
FEATURE
Interventional Cardiology
ommentary
More evidence in
favor of the use
of DES in patients The study investigators are to be commended on this com-
undergoing SVG-PCI
prehensive report on SVG-PCI in a large patient population
(2472 patients), which utilized excellent statistical analyses.
A few findings do, however, merit comment. The low complica-
tion rates, particularly the low rates of periprocedural MI (.5%),
seem quite low and may reflect self-reporting and incomplete as-
sessment of troponin-measured myocardial necrosis. SVG age is
not reported, and it is possible that there may be differences be-
tween the 2 groups that could influence event rates. There is a clear
disconnect between the similar MI rates, yet notable difference in
observed mortality rates. Although the authors used propensity-
matched analysis, this at least suggests the possibility that some
factors could not be accounted for. Perhaps DES were preferen-
tially placed in patients judged to be healthier and more apt to
tolerate prolonged dual antiplatelet therapy (DAPT), while BMSs
were preferentially placed in patients judged to be more frail and
less likely to tolerate prolonged DAPT. Somewhat along these lines,
no data are presented on duration of DAPT. Although it is unlikely
that additional months or even several years of DAPT would sig-
nificantly impact overall mortality to the degree seen in this study
(if at all), this nevertheless is an additional consideration in inter-
preting the results of this study.
Numerous prior cohort studies, several randomized trials, and
meta-analyses have compared outcomes in patients undergoing
SVG-PCI treated with either DES or BMS.4 In the ISAR-CABG
study, 610 patients undergoing SVG-PCI were randomized to treat-
ment with either DES or BMS. The composite primary end point
of death, MI, and target lesion revascularization (TLR) at 1 year
occurred in 15% of DES-treated patients and 22% of BMS-treated
patients (HR, .64; CI, .44-.94; P = .02). TLR was halved with DES
treatment (7% vs 13%; HR, .49; CI, .28-.86; P = .01), and there
were no significant differences in definite or probable stent throm-
bosis, MI, or all-cause mortality.5 In a meta-analysis of studies
comparing DES with BMS for SVG-PCI, Wiisanen and colleagues
reported that patients treated with DES had a lower risk of TLR
(odds ratio [OR], .57; CI, .40-.82), major adverse cardiac events
(OR, .61; CI, .42-.79), and mortality (OR, .75; CI, .59-.96).4
The 2011 American College of Cardiology Foundation / Ameri-
can Heart Association / Society for Cardiovascular Angiography
and Interventions (ACC/AHA/SCAI) Guideline for Percutaneous
Coronary Intervention does not make a specific formal recommen-
dation regarding the use of DES in SVG-PCI, but does list SVG-
PCI as a clinical situation in which DES are generally preferred
over BMS.6 The 2014 European Society of Cardiology/European
Association for Cardio-Thoracic Surgery (ESC/EACTS) Guidelines
on Myocardial Revascularization similarly do not give a specific
formal recommendation regarding choice of stent in SVG-PCI, but
they do note that the increased efficacy and safety of new-genera-
tion DES have enabled their unrestricted use in patients with coro-
nary artery disease and an indication for PCI, including patients
with SVG lesions. Therefore, they should be considered by default
in all clinical conditions and lesion subsets.7
Thus, the propensity of data and expert opinion favors the use of
DES in patients undergoing PCI. This latest analysis by Aggarwal
and colleagues does not, at the very least, contradict this conflu-
ence of data and opinion; in fact, it seems to further support it.
Additional data will likely be available at the end of 2016 when
results of the VA Cooperative Study Drug-Eluting Stents vs Bare
Metal Stents in Saphenous Vein graft Angioplasty (DIVA) study8
become available.
References
1.Taggart DP, Banning AP. Stents and failing vein grafts: are we any wiser
after ISAR? Lancet. 2011;378(9796):1054-1055.
2. FitzGibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR.
Coronary bypass graft fate and patient outcome: angiographic follow-up
of 5,065 grafts related to survival and reoperation in 1,388 patients during
25 years. J Am Coll Cardiol. 1996;28(3):616-626.
3.Aggarwal V, Stanislawski MA, Maddox TM, et al. Safety and effective-
ness of drug-eluting versus bare-metal stents in saphenous vein bypass graft
percutaneous coronary intervention. J Am Coll Cardiol. 2014;64:1825-
1836.
4. Wiisanen ME, Abdel-Latif A, Mukherjee D, Ziada KM. Drug-elut-
ing stents versus bare-metal stents in saphenous vein graft interven-
tions: a systematic review and meta-analysis. JACC Cardiovasc Interv.
2010;3(12):1262-1273.
5. Mehilli J, Pache J, Abdel-Wahab M, et al. Drug-eluting versus bare-metal
stents in saphenous vein graft lesions (ISAR-CABG): a randomised con-
trolled superiority trial. Lancet. 2011;17;378(9796):1071-1078.
6. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI
Guideline for Percutaneous Coronary Intervention. A report of the Ameri-
can College of Cardiology Foundation/American Heart Association Task
Force on Practice Guidelines and the Society for Cardiovascular Angiogra-
phy and Interventions. J Am Coll Cardiol. 2011;58(24):e44-e122.
7. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on
myocardial revascularization: The Task Force on Myocardial Revascular-
ization of the European Society of Cardiology (ESC) and the European
Association for Cardio-Thoracic Surgery (EACTS). Developed with the
special contribution of the European Association of Percutaneous Cardio-
vascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541-2619.
8. Drug-Eluting Stents vs. Bare Metal Stents In Saphenous Vein Graft
Angioplasty (DIVA) study. Clinical trials website. http://clinicaltrials.gov/
show/NCT01121224.
About the Author
Glenn n. levine, MD, FAHA, FACC, is professor of medicine at Bay-
lor College of Medicine, and director of the Cardiac Care Unit at
Michael E. DeBakey Medical Center in Houston, Texas. He received
his MD from Columbia University College of Physicians and Sur-
geons in New York City and completed postdoctoral training in
advanced cardiovascular imaging at Baylor College of Medicine/
Texas Heart Institute. Dr Levine’s internship, residency, and fellow-
ships in interventional cardiology and cardiology were at Boston
University Medical Center. He has coauthored numerous published
clinical trials, guidelines, and textbook chapters.