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Cardiovascular Safety During and After Use of Phentermine and Topiramate

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Context Increases in heart rate were seen during the clinical program for fixed-dose combination phentermine (PHEN) and topiramate (TPM), an oral medication indicated for weight management, but the effect on cardiovascular (CV) outcomes is uncertain. Objective The aim of the study was to determine the extent to which rates of major adverse cardiovascular events (MACE) while patients were using PHEN and TPM (including fixed dose) differed from MACE rates during unexposed periods. Design Retrospective cohort study Setting MarketScan, US insurance billing data Patients or other participants Patients over 18 years with at least 6 months continuous enrollment in database before taking PHEN and/or TPM or after stopping these medications Intervention(s) PHEN and TPM, taken separately and together (including fixed dose) Main outcome measure(s) MACE, a composite of hospitalization for acute myocardial infarction and stroke, and in-hospital CV death Results Because the outcomes are rare and the duration of medication use was brief, there were few events. Rates of MACE among current users of PHEN/TPM, fixed-dose PHEN/TPM, and PHEN were lower than those among unexposed former users, whereas the rate of MACE among current users of TPM was higher than among unexposed former users (incidence rate ratio [95% confidence interval]: PHEN/TPM 0.57 [0.19-1.78]; fixed-PHEN/TPM 0.24 [0.03-1.70]; PHEN 0.56 [0.34-0.91]; TPM 1.58 [1.33-1.87]). Conclusions Overall, the data indicate no increased risk of MACE for current PHEN/TPM users, but confidence intervals for the PHEN/TPM groups were broad, indicating that the data were compatible with a wide range of possible values.
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CLINICAL RESEARCH ARTICLE
Cardiovascular Safety During and After Use of
Phentermine and Topiramate
Mary E. Ritchey,
1
Abenah Harding,
1
Shannon Hunter,
1
Craig Peterson,
2
Philip T. Sager,
3
Peter R. Kowey,
4
Lan Nguyen,
2
Steven Thomas,
1
Miguel Cainzos-Achirica,
5
Kenneth J. Rothman,
6
Elizabeth B. Andrews,
1
and Mary S. Anthony
1
1
RTI Health Solutions, Research Triangle Park, North Carolina 27709-2194;
2
VIVUS, Inc., Campbell,
California 95008;
3
Stanford University School of Medicine, Stanford, California 94305;
4
Sidney Kimmel
Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107;
5
RTI Health Solutions,
08028 Barcelona, Spain; and
6
RTI Health Solutions, Waltham, Massachusetts 02452-8413
ORCiD numbers: 0000-0003-0304-9304 (M. E. Ritchey).
Context: Increases in heart rate were seen during the clinical program for fixed-dose combination
phentermine (PHEN) and topiramate (TPM), an oral medication indicated for weight management;
however, the effect on cardiovascular (CV) outcomes is uncertain.
Objective: The aim of the present study was to determine the extent to which the rates of major
adverse CV events (MACE) in patients using PHEN and TPM (including fixed dose) differed from the
MACE rates during unexposed periods.
Design: Retrospective cohort study.
Setting: MarketScan, US insurance billing data.
Patients or Other Participants: Patients aged .18 years with $6 months of continuous enrollment in
the database before taking PHEN and/or TPM or after stopping these medications.
Interventions: PHEN and TPM, taken separately and together (including fixed dose).
Main Outcome Measures: MACE, a composite of hospitalization for acute myocardial infarction and
stroke and in-hospital CV death.
Results: Because the outcomes are rare and the duration of medication use was brief, few events
occurred. The MACE rates among current users of PHEN/TPM, fixed-dose PHEN/TPM, and PHEN were
lower than those among unexposed former users. In contrast, the rate of MACE among current
users of TPM was greater than among unexposed former users [incidence rate ratio: PHEN/TPM,
0.57; 95% CI, 0.19 to 1.78; fixed-PHEN/TPM, 0.24; 95% CI, 0.03 to 1.70; PHEN, 0.56; 95% CI, 0.34 to
0.91; TPM, 1.58; 95% CI, 1.33 to 1.87).
Conclusions: Overall, the data indicated no increased risk of MACE for current PHEN/TPM users;
however, the 95% CIs for the PHEN/TPM groups were broad, indicating that the data were compatible
with a wide range of possible values. (J Clin Endocrinol Metab 104: 513522, 2019)
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA
Copyright © 2019 Endocrine Society
This article has been published under the terms of the Creative Commons Attribution
License (CC BY; https://creativecommons.org/licenses/by/4.0/).
Received 8 May 2018. Accepted 18 September 2018.
First Published Online 21 September 2018
Abbreviations: AMI, acute myocardial infarction; CV, cardiovascular; FDA, Food and Drug
Administration; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical
Modification; IRD, incidence rate difference; IRR, incidence rate ratio; MACE, major
adverse cardiovascular events; PHEN, phentermine; TPM, topiramate.
doi: 10.1210/jc.2018-01010 J Clin Endocrinol Metab, February 2019, 104(2):513522 https://academic.oup.com/jcem 513
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Nearly 40% of adults in the United States are obese.
The prevalence is even greater among older adults
and has been increasing during the past 15 years (1).
Obese individuals have greater mortality rates than the
general population and an increased risk of overall,
cardiovascular (CV)-related, and diabetes-related mor-
tality (2). In recent years, several medications have re-
ceived US Food and Drug Administration (FDA) approval
as adjuncts to diet and lifestyle modifications for the
management of obesity. One such medication is a fixed-
dose combination of phentermine and extended-release
topiramate (Qsymia
®
, Vivus, Inc.). Phentermine (PHEN)
is a stimulant and is indicated for short-term use in weight
management. It acts as an appetite suppressant via the
central nervous system. Topiramate (TPM) is an anti-
convulsant indicated for use in the treatment of migraine
and epilepsy. One of the known effects of TPM is a de-
crease in appetite. Consequently, it is sometimes pre-
scribed off-label for weight loss (3). Typical dosing of
PHEN is 15 to 37.5 mg/d. The typical dosage of TPM is
100 mg/d for migraine or 50 to 400 mg/d for epilepsy. The
approved fixed-dose combination (fixed-PHEN/TPM)
contains PHEN doses from 3.75 to 15 mg and TPM
doses from 23 to 92 mg for daily administration.
The results from two randomized clinical trials and
one 2-year extension study showed a slight increase in the
average heart rate for those taking fixed-PHEN/TPM
(46). For those taking high-dose fixed-PHEN/TPM
(PHEN 15 mg/TPM 92 mg), average heart rate in-
creased from baseline by 1.2 to 1.7 beats per minute. In
these same trials, several traditional CV risk factors were
improved with fixed-PHEN/TPM treatment, specifically
decreased body weight and body mass index, lower
systolic and diastolic blood pressure, lower low-density
lipoprotein cholesterol and plasma triglyceride concen-
trations, and lower fasting blood glucose levels.
These studies provided limited information on the CV
safety of fixed-PHEN/TPM and its component medica-
tions as they are currently used within clinical practice.
Therefore, a randomized, prospective postmarketing
outcome study of major adverse CV events (MACE) was
requested by a regulatory agency. However, usage of
fixed-PHEN/TPM is low, and performance of a ran-
domized study of medications in a postmarket setting is
difficult, especially for CV event outcomes. With low
drug uptake and rare outcomes, a retrospective obser-
vational database study is an efficient method to generate
information on the safety of fixed-PHEN/TPM in usual
clinical practice in a much shorter time than would be
possible with a prospective study.
The aim of the present study was to evaluate the
risk of MACE during current use periods of PHEN,
TPM, PHEN/TPM (including the two drugs separately
and in a fixed-dose combination), and fixed-PHEN/TPM
(only the fixed-dose combination) vs unexposed periods
among former users of PHEN, TPM, or both PHEN and
TPM (Fig. 1).
Subjects and Methods
Study design and population
The present retrospective cohort study was conducted in the
Truven Health MarketScan Databases (Commercial and
Medicare Supplemental administrative claims). MarketScan
was chosen as the data source because it had the largest number
of fixed-PHEN/TPM users among the databases evaluated
during an earlier feasibility assessment. In addition, it has a
Figure 1. Schematic of cohorts with comparisons indicated.
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suitable breadth of information available about patients and the
ability to capture the medication exposures and CV outcomes
reliably. A prospective study with the number of patients available
in the present database would not be feasible because of the large
study size and long duration required for CV outcome studies.
The data span the period beginning 1 July 2012, the month
Qsymia was approved by the US FDA, through 30 September
2015. Patients were eligible for study entry if they were
aged $18 years and had been enrolled in MarketScan for
$6 months and met the criteria to be included as a current or
former user of PHEN, TPM, PHEN/TPM, and/or fixed-PHEN/
TPM (Fig. 2). Depending on their medication use, patients
could simultaneously contribute time to more than one of these
variously defined current-use medication cohorts. For example,
patients prescribed fixed-PHEN/TPM contributed to the
current-use fixed-PHEN/TPM, PHEN, TPM, and PHEN/TPM
medication cohorts simultaneously.
We used the periods corresponding to current use of med-
ications as the exposed time at risk. We compared the rates
during those periods with the rates among the unexposed pe-
riods among former users of the study medications. Because
these cohorts are dynamic, with patients moving in and out of
them, a given patient could contribute to both current use of
medication and, when no longer taking the medication, to the
unexposed time at risk. However, not all patients contributed to
both current-use and unexposed periods. The index date for
current-use periods was the date of the first prescription dis-
pensed after a $180-day period free of exposure (for the initial
entry into the cohort) or after a gap of .60 days (for subsequent
use). The index date for unexposed periods was the first day on
which eligibility criteria were met and .60 continuous days
without exposure to any of the study medications. Patients
could contribute time to multiple current-use periods and un-
exposed periods if they had started, stopped, or switched study
medications. Patients were excluded if they had undergone a
surgical procedure for weight loss or dispensing of fenfluramine
or dexfenfluramine before their first index date. In addition,
because TPM is indicated for seizures and epilepsy, we excluded
patients who had been dispensed TPM without PHEN if they
had a diagnosis for seizures or epilepsy within 30 days before
the initial TPM prescription, or if they had been prescribed daily
doses of .100 mg of TPM (doses associated with epilepsy).
The decision to compare outcomes during periods of current
exposure with those during unexposed periods among former
users of these same medications rather than with nonusers was
determined from two major considerations. First, because the
underlying condition of obesity or overweight status is often not
captured with the diagnosis codes in claims data, it is difficult to
match a nonuser cohort to current users of these drugs by
obesity status. Using nonexposed periods in former users as a
comparison achieves partial balance for obesity status. Second,
because the signal of potential concern with Qsymia is increased
heart ratean effect that does not persist after the drug is
withdrawnthe potential for carryover effects beyond current
use was considered remote.
Key variables
The current-use periods of each medication began on the
index date of the dispensing of that medication and continued
until 7 days after the end of the last dayssupply of the last
dispensing (i.e., 37 days after the last prescription fill). Un-
exposed periods began 60 days after the end of the dayssupply
of the last medication dispensing and continued until a new
study medication was dispensed or the end of patient follow-up.
Outcomes were defined by the hospital admission and
principal diagnosis codes using International Classification of
Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).
Acute myocardial infarction (AMI) was defined using ICD-9-
CM codes 410.x0 and 410.x1, and stroke was defined using
ICD-9-CM codes 430, 431, 433.x1, 434 (excluding 434.x0),
and 436 (7). These codes have been validated in claims data-
bases with positive predictive values ranging from 76% to 94%
(7, 8). In-hospital CV-related death was identified using the
discharge status diedand either a principal discharge di-
agnosis of AMI, stroke, heart failure, coronary heart disease, or
cerebrovascular disease or a procedure code during the hospi-
talization indicating CV revascularization. The composite endpoint
Figure 2. Schematic of risk periods.
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of hospitalization for AMI or stroke and in-hospital CV-related
death was MACE. Out-of-hospital death was not available from the
data source and was thus not included in the present study.
Covariates were assessed across all available look-back time,
which was $180 days before each index date (9). Covariates
included age at index date, sex, and hospitalization for CV
disease, length of hospitalization, duration of look-back time,
comorbidities defined by diagnoses, and history of medication
use. Comorbidity diagnoses were assessed via ICD-9-CM codes
and included obesity, previous AMI, previous stroke, transient
ischemic attack, hypertension, heart failure, unstable angina,
peripheral vascular disease, coronary heart disease, cerebro-
vascular disease, hyperlipidemia, prediabetes, diabetes mellitus,
chronic kidney disease, migraine, and sleep apnea. Medication
history was defined using National Drug Codes and the fol-
lowing medications were included as covariates: antihyper-
tensive agents, lipid-modifying agents, anticoagulants, other
CV drugs (e.g., vasodilating agents), insulin, other antidiabetic
drugs, antiobesity drugs other than the ones included in the
study, epilepsy drugs (other than TPM), migraine drugs (other
than TPM), and/or prescription aspirin. In addition, the cal-
endar year and month of the index date were collected.
Statistical analysis
Descriptive statistics for demographic variables and relevant
covariates were obtained for each current-use medication co-
hort (PHEN/TPM, fixed-PHEN/TPM, PHEN, and TPM) and
for the unexposed former-user cohort.
The crude incidence rates, crude and adjusted incidence rate
ratios (IRRs), and crude and adjusted incidence rate differences
(IRDs) for each study outcome were calculated separately for
current-use periods of each medication and for the unexposed
periods.
Propensity score methods were used to control for confounding.
Three separate propensity score models were developed for com-
parison of current use of each of the four medication/combinations
[PHEN/TPM (including fixed-PHEN/TPM), PHEN, and TPM] vs
unexposed former users. Propensity score models were created by
assessing the effects of each potential covariate on the composite
MACE outcome. The balance of covariates between current users
and the unexposed was assessed using standardized differences.
Subjects with extreme propensity scores ,2.5th or .97.5th per-
centile were trimmed before stratification into deciles based on the
distribution of current users. Stratum-specific IRRs and IRDs were
calculated and summary IRR and IRD were calculated using the
Mantel-Haenszel approach outlined in Rothman et al. (10).
We conducted sensitivity and bias analyses to determine
whether the choices made for variable definitions and the com-
parator group were affecting the results. Sensitivity analyses were
conducted for cohorts in which $10 MACE outcomes had oc-
curred during the current-use periods. Analyses included assessing
the effect of potential unmeasured confounders (e.g., smoking) via
proxy variables (e.g., diagnosis of chronic obstructive pulmonary
disease), assessing an alternative outcome of MACE that includes
hospitalization for heart failure, limiting the length of the current-
use periods and unexposed periods to a maximum of 6 months,
requiring 180 days between prescriptions to initiate a subsequent
current-use period, assuming that only a proportion of CV-related
deaths (e.g., 30%) was captured during hospitalizations (in
contrast to deaths occurring outside the hospital) for current user
cohorts. In addition, current users vs the unexposed were assessed
in mutually exclusive medication cohorts (e.g., comparing current-
use periods of PHEN/TPM to unexposed periods among former
users of PHEN/TPM).
Results
Patient demographics
Patients included and excluded from the present study
are shown in Fig. 3. The characteristics for each patient at
the first entry into each current-use medication cohort and
into the unexposed cohort are listed in Table 1. More than
500,000 patients were included in the present study; 14,586
contributed time at risk to the fixed-PHEN/TPM cohort
and an additional 4598 to the cohort of PHEN/TPM as
individual medications. A single patient could be included
in multiple cohorts, corresponding to multiple columns in
Table 1. On average, patients contributed 1.6 current-use
periods within a single medication cohort and 2.6 un-
exposed periods. There were 16,365 current-use periods,
averaging 1.9 months among patients taking fixed-PHEN/
TPM; 21,405 current-use periods, averaging 1.9 months
among patients taking PHEN/TPM; 165,737 current-use
periods, averaging 1.7 months for PHEN; 373,753 current-
use periods, averaging 2.1 months for TPM; and 472,630
unexposed periods, averaging 7.9 months.
For the unexposed comparator group, 73.8% had
previously used TPM, 26.3% had previously used PHEN,
and only 2.4% had previously used fixed-PHEN/TPM.
Current users of any of the medications were less likely
than the unexposed to have epilepsy. The prevalence of
comorbidities and other medication use among the un-
exposed cohort was most similar to that among current
TPM users. Both the unexposed cohort and current users
of TPM had a greater baseline history of stroke, transient
ischemic attack, migraine, and epilepsy compared with the
current users of PHEN/TPM or PHEN.
Most patients initiating PHEN/TPM (76%) were fixed-
PHEN/TPM users. Compared with the unexposed cohort,
patients initiating PHEN/TPM were older and more likely to
have a recorded history of obesity. In addition, patients
initiating PHEN/TPM were more likely than the unexposed
cohort to have hypertension, hyperlipidemia, diabetes, and
sleep apnea.
Unadjusted incidence rates
The number of events, person-time of follow-up, un-
adjusted incidence rates, and 95% confidence intervals
(CIs) for MACE and its components (hospitalization for
AMI or stroke and in-hospital CV-related death) are listed
in Table 2. The unadjusted incidence rate of MACE among
current users of PHEN/TPM and fixed-PHEN/TPM was
lower than the rate of MACE among the unexposed co-
hort. However, the number of events was small, producing
considerable statistical variability (as evidenced by wide
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95% CIs). The current use of PHEN was associated with
lower rates of MACE compared with the unexposed cohort.
The current use of TPM was associated with greater rates of
MACE compared with that in the unexposed cohort.
The incidence rates of MACE were greater among
both current users of TPM and the unexposed cohort
relative to other current-use cohorts. The rates of AMI
and stroke were greater than the rates for in-hospital CV
death in all current-use and unexposed periods. The
average length of the current-use periods for all medi-
cations ranged from 2.1 to 2.5 months.
Results from adjusted analyses of MACE and
individual components
Propensity score adjustment created a reasonable
balance between the current-use periods and unexposed
Figure 3. Flow diagram of selection into study cohorts.
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periods for all variables included in the propensity score
models. The number of events and person-years of
follow-up after propensity score stratification and trim-
ming and the adjusted IRRs, IRDs, and 95% CIs for all
outcomes are listed in Table 3. After propensity score
adjustment, the rates of MACE among current users of
PHEN/TPM, fixed-PHEN/TPM, and PHEN remained
lower than those among the unexposed cohort, and the
rate of MACE among current users of TPM remained
greater than that among the unexposed cohort. Com-
pared with the crude IRRs and IRDs, the propensity
score-adjusted measures were closer to the null (IRR:
PHEN/TPM, 0.57; 95% CI, 0.19 to 1.78; fixed-PHEN/
TPM, 0.24; 95% CI, 0.03-1.70; PHEN, 0.56; 95% CI,
0.34 to 0.91; TPM, 1.58; 95% CI, 1.33 to 1.87). No
substantial differences were found in the IRR and IRD
between the unadjusted and adjusted results, indicating
that the net amount of confounding was modest.
Just as with the crude results, the rates of AMI and
stroke during the current-use periods of PHEN/TPM and
fixed-PHEN/TPM were lower than those during the
unexposed periods. The current users of PHEN had
lower rates of AMI (IRR, 0.51; 95% CI, 0.0.26 to 1.00)
and stroke (IRR, 0.58; 95% CI, 0.27 to 1.24) compared
with the unexposed cohort. In contrast, the rate of CV
death was similar for current users and the unexposed
cohort (IRR, 1.03; 95% CI, 0.12 to 8.67). The current
users of TPM had greater rates of stroke (IRR, 2.81; 95%
Table 1. Baseline Patient Demographics, Medical Comorbidities, and Medications
Characteristic
Current-Use Periods
Unexposed
(n = 386,136)
PHEN/TPM
(n = 19,184)
Fixed-PHEN/TPM
(n = 14,586)
PHEN
(n = 124,334)
TPM
(n = 316,388)
Age, y 46.5 610.94 47.3 610.81 43.8 611.22 43.2 613.32 43.7 613.00
Age categories, n (%)
1837 y 4161 (21.7) 2868 (19.7) 37,691 (30.3) 109,988 (34.8) 127,586 (33.0)
3849 y 7093 (37.0) 5270 (36.1) 46,482 (37.4) 102,348 (32.3) 127,824 (33.1)
$50 y 7930 (41.3) 6448 (44.2) 40,161 (32.3) 104,052 (32.9) 130,726 (33.9)
Sex, n (%)
Male 3747 (19.5) 2964 (20.3) 21,358 (17.2) 55,765 (17.6) 66,541 (17.2)
Female 15,437 (80.5) 11,622 (79.7) 102,976 (82.8) 260,623 (82.4) 319,595 (82.8)
Medical history and
comorbid conditions, n (%)
Obesity 10,066 (52.5) 8147 (55.9) 45,339 (36.5) 72,451 (22.9) 104,657 (27.1)
AMI 54 (0.3) 45 (0.3) 267 (0.2) 1831 (0.6) 1983 (0.5)
Stroke 141 (0.7) 111 (0.8) 688 (0.6) 8595 (2.7) 9378 (2.4)
Transient ischemic attack 150 (0.8) 116 (0.8) 745 (0.6) 7575 (2.4) 8278 (2.1)
Hypertension 8529 (44.5) 6832 (46.8) 41,659 (33.5) 107,386 (33.9) 130,473 (33.8)
Heart failure 213 (1.1) 176 (1.2) 950 (0.8) 5626 (1.8) 6309 (1.6)
Unstable angina 152 (0.8) 124 (0.9) 663 (0.5) 3473 (1.1) 3803 (1.0)
Peripheral vascular disease 551 (2.9) 456 (3.1) 2037 (1.6) 8528 (2.7) 9940 (2.6)
Coronary heart disease 997 (5.2) 839 (5.8) 4170 (3.4) 18,672 (5.9) 21,440 (5.6)
Cerebrovascular disease 733 (3.8) 583 (4.0) 3201 (2.6) 24,681 (7.8) 28,070 (7.3)
Hyperlipidemia 8927 (46.5) 7197 (49.3) 43,124 (34.7) 107,087 (33.8) 132,853 (34.4)
Prediabetes 1703 (8.9) 1430 (9.8) 6936 (5.6) 17,031 (5.4) 20,439 (5.3)
Diabetes 3974 (20.7) 3315 (22.7) 15,741 (12.7) 39,957 (12.6) 48,405 (12.5)
Chronic kidney disease 340 (1.8) 284 (1.9) 1299 (1.0) 6167 (1.9) 7890 (2.0)
Sleep apnea 3205 (16.7) 2652 (18.2) 12,733 (10.2) 36,389 (11.5) 44,237 (11.5)
Migraine 1914 (10.0) 1261 (8.6) 11,165 (9.0) 124,960 (39.5) 159,307 (41.3)
Epilepsy 99 (0.5) 71 (0.5) 636 (0.5) 6035 (1.9) 14,704 (3.8)
Medication history, n (%)
Antihypertensive agents 9283 (48.4) 7340 (50.3) 46,755 (37.6) 133,538 (42.2) 163,447 (42.3)
Lipid-modifying agents 5499 (28.7) 4516 (31.0) 24,185 (19.5) 67,373 (21.3) 82,201 (21.3)
Anticoagulant agents 808 (4.2) 681 (4.7) 3528 (2.8) 15,433 (4.9) 17,996 (4.7)
Other CV system drugs 2 (0.0) 2 (0.0) 7 (0.0) 62 (0.0) 68 (0.0)
Insulin 945 (4.9) 833 (5.7) 2968 (2.4) 8712 (2.8) 9835 (2.5)
Other antidiabetic drugs 4319 (22.5) 3541 (24.3) 16,883 (13.6) 36,417 (11.5) 45,103 (11.7)
Other antiobesity drugs 2851 (14.9) 2293 (15.7) 13,989 (11.3) 40,640 (12.8) 39,867 (10.3)
Aspirin 79 (0.4) 68 (0.5) 315 (0.3) 1210 (0.4) 1465 (0.4)
Migraine drugs 1645 (8.6) 1185 (8.1) 9233 (7.4) 93,252 (29.5) 116,409 (30.1)
Epilepsy drugs 2663 (13.9) 2032 (13.9) 14,917 (12.0) 84,545 (26.7) 100,743 (26.1)
TPM 2010 (10.5) 672 (4.6) 7789 (6.3) 56,643 (17.9) 284,999 (73.8)
PHEN 3400 (17.7) 1521 (10.4) 33,773 (27.2) 10,841 (3.4) 101,712 (26.3)
Qsymia 347 (1.8) 331 (2.3) 397 (0.3) 334 (0.1) 9434 (2.4)
Data presented as mean 6SD or n (%).
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CI, 2.26 to 3.50) and lower rates of AMI (IRR, 0.79;
95% CI, 0.59 to 1.07) and CV death (IRR, 0.35; 95% CI,
0.08 to 1.45) compared with the unexposed cohort.
Event numbers, especially for CV death, were small, and
the 95% CIs around the effect measures for components
of MACE were wide for all medication cohorts.
Sensitivity and bias analyses
We conducted several sensitivity and bias analyses
among the PHEN cohort and TPM cohort, both of which
had .10 MACE outcomes during the current-use pe-
riods. These sensitivity analyses varied with the time after
last drug dispensing to the end of the exposure period,
extended the required time period without the drug be-
fore initiating subsequent use, limited the current-use
period to only the first 6 months of medication use,
and assessed the effect of assessing only in-hospital death.
The results were qualitatively similar to the primary
results for each of these analyses.
Sensitivity analyses also were conducted with mutu-
ally exclusive, current-use medication cohorts, and un-
exposed periods among former users of PHEN, TPM,
and PHEN/TPM. The results of these analyses were
directionally similar to the results listed in Table 3, but in
all cases were closer to the null (Table 4). For example,
the IRR for the primary results for current users of
Table 2. Crude Incidence Rates Per 1000 Person-Years and 95% CIs for MACE and Components of
This Outcome
Variable
Current Use Periods
Unexposed
(n = 386,136)
PHEN/TPM
(n = 19,184)
Fixed-PHEN/TPM
(n = 14,586)
PHEN
(n = 124,334)
TPM
(n = 316,388)
Person-years 3245 2587 24,107 64,607 310,665
MACE
Events, n 3 1 22 218 622
Events/1000 person-years 0.92 (0.192.70) 0.39 (0.012.15) 0.91 (0.571.38) 3.37 (2.943.85) 2.00 (1.852.17)
AMI
Events, n 1 0 11 62 335
Events/1000 person-years 0.31 (0.011.72) 0.00 (0.001.43) 0.46 (0.230.82) 0.96 (0.741.23) 1.08 (0.971.20)
Stroke
Events, n 2 1 10 154 258
Events/1000 person-years 0.62 (0.072.23) 0.39 (0.012.15) 0.41 (0.200.76) 2.38 (2.022.79) 0.83 (0.730.94)
CV-related death
Events, n 0 0 1 2 29
Events/1000 person-years 0.00 (0.001.14) 0.00 (0.001.43) 0.04 (0.000.23) 0.03 (0.000.11) 0.09 (0.060.13)
Data in parentheses are 95% CIs.
Table 3. Adjusted IRRs and IRDs for MACE and Components of This Outcome
Variable
PHEN/TPM Fixed-PHEN/TPM PHEN TPM
Current
Use
Unexposed
(Reference)
Current
Use
Unexposed
(Reference)
Current
Use
Unexposed
(Reference)
Current
Use
Unexposed
(Reference)
Person-years 2820 232,470 2207 217,665 22,218 251,807 60,889 291,147
MACE
Events, n 3 424 1 395 17 423 186 539
IRR (95% CI) 0.57 (0.19 to 1.78) 0.24 (0.03 to 1.70) 0.56 (0.34 to 0.91) 1.58 (1.33 to 1.87)
IRD (95% CI) 20.79 (22.03 to 0.44) 21.43 (22.37 to 20.50) 20.62(21.02 to 20.22) 1.11 (0.64 to 1.57)
AMI
Events, n 1 240 0 225 9 241 51 296
IRR (95% CI) 0.35 (0.05 to 2.52) 0.00 (0.00 to NC) 0.51 (0.26 to 1.00) 0.79 (0.59 to 1.07)
IRD (95% CI) 20.66 (21.37 to 0.06) 21.02 (21.20 to 20.85) 20.39 (20.68 to 20.10) 20.22 (20.48 to 0.04)
Stroke
Events, n 2 167 1 154 7 167 133 217
IRR (95% CI) 0.89 (0.22 to 3.53) 0.55 (0.08 to 3.85) 0.58 (0.27 to 1.24) 2.81 (2.26 to 3.50)
IRD (95% CI) 20.09 (21.10 to 0.92) 20.37 (21.29 to 0.54) 20.23 (20.49 to 0.03) 1.38 (1.01 to 1.76)
CV-related death
Events, n 0 17 0 16 1 15 2 26
IRR (95% CI) 0.00 (0.00 to NC) 0.00 (0.00 to NC) 1.03 (0.12 to 8.67) 0.35 (0.08 to 1.45)
IRD (95% CI) 20.04 (20.07 to 20.02) 20.04 (20.06 to 20.02) 0.00 (20.09 to 0.09) 20.06 (20.12 to 0.00)
Data are adjusted for propensity score decile after trimming.
Abbreviation: NC, not calculated.
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PHEN/TPM vs unexposed former users of any medica-
tion was 0.57 (95% CI, 0.19 to 1.78), and the IRR for the
mutually exclusive current-use vs unexposed PHEN/
TPM comparison was 0.93 (95% CI, 0.20 to 4.32).
The number of events was smaller for each of these
analyses than those in the primary results, leading to
wider 95% CIs.
Discussion
The rationale for including the unexposed periods among
former users rather than nonusers as the referent group
was that the CV risk is expected to be greater in an obese
population than in a nonobese population. However, it
was not practical to identify an untreated obese population
in an administrative claims database because of incon-
sistent coding of this condition. By restricting the com-
parison rates to periods after the use of PHEN, TPM, or
PHEN/TPM, we identified a population that was not
currently exposed to the medications of interest (PHEN,
TPM) but was expected to have similar CV risk to the
obese population currently using these medications. Al-
though the study did not use self-matching of different
periods, many subjects contributed to both the treated and
the untreated cohorts, achieving partial self-matching with
its control of factors that remain constant over time in an
individual.
We controlled for confounding from the differences
that remained between the treatment and comparator
groups using propensity score modeling and stratifica-
tion. Sensitivity analyses provided further insight into the
robustness of the results to the decisions made during the
design of the study. The results were similar for PHEN
and TPM when the MACE outcome was modified to
include heart failure, when assuming that only a portion
of deaths were captured during current-use periods,
when assessing only the first 6 months of each current-use
or unexposed period, and when assessing other potential
confounders (e.g., proxy for smoking). The results from
sensitivity analyses were generally closer to the null, and,
because of the more restricted follow-up time, the 95%
CIs were wider. In these analyses, the crude results
were not appreciably different from the adjusted re-
sults, suggesting little confounding. Comparisons of
mutually exclusive current-use periods vs unexposed
periods among each medication cohort led to few events
for PHEN/TPM (,10 MACE events total) and wide
95% CIs.
The present study included a large number of patients
treated for several years within a US claims data source
representative of the patient experience with PHEN/TPM
in the United States. The FDA has acknowledged that
observational studies using databases are an effective
method to generate information on the safety of medi-
cations as used in usual clinical practice within a much
shorter time than would be possible with a prospective
study (11). The present study was also prespecified via
protocol and conducted in accordance with both regu-
latory and international society guidelines for observa-
tional database studies (1215). It included outcome
measures previously validated within claims data. In an
era in which regulators are calling for increased use of
real-world evidence for regulatory decision-making, the
present database analysis has provided timely data on a
large number of patients in a manner that is actionable
(e.g., can rule out doubling of MACE outcomes among
users of PHEN/TPM). Furthermore, the insights gained
from the present study were obtained within several
months, rather than over several years.
The reason for the greater risk of stroke among current
TPM users compared with former TPM users is not
obvious. It might be a real difference, a chance finding, or
an unidentified bias. The incidence rates of MACE,
driven by the rates of stroke, were greater for both
current users of TPM and the unexposed after the use of
TPM compared with other medications. The exclusion
criteria specific to TPM imply that these patients do not
constitute all patients prescribed TPM. Furthermore, the
Table 4. Sensitivity Analysis: Event Counts, Person-Time, Propensity ScoreAdjusted Incidence Rate Ratio,
and Incidence Rate Difference for MACE Comparing Current Use and Unexposed Former Users of Each
(Mutually Exclusive) Medication
Cohort Events, n Person-Years IRR (95% CI) IRD (95% CI)
PHEN/TPM
Current use 2 2901.9 0.93 (0.20 to 4.32) 20.06 (21.19 to 1.08)
Unexposed 7 9146.1 Reference Reference
PHEN
Current use 17 18,636.2 0.78 (0.46 to 1.30) 20.27(20.77 to 0.23)
Unexposed 93 77,797.2 Reference Reference
TPM
Current use 188 55,714.3 1.49 (1.26 to 1.77) 1.11 (0.58 to 1.63)
Unexposed 457 201,561.8 Reference Reference
Each current-use group was compared with former users of the same medication.
520 Ritchey et al CV Safety With Phentermine and Topiramate J Clin Endocrinol Metab, February 2019, 104(2):513522
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exclusion criteria specific to TPM were designed to remove
patients with epilepsy from the study, because they have
an increased risk of stroke. However, more patients with a
history of antiepileptic drug use were present in the TPM
cohort than in the PHEN cohort (27% vs 12%) (16).
Perhaps the subset of TPM users included were at an
increased risk of this outcome in a way that was in-
adequately measured in the present study (e.g., they might
have had increased systolic blood pressure and were thus
prescribed TPM because of its known effect of decreasing
systolic blood pressure and/or the attempt to control for an
epilepsy diagnosis and medication use was insufficient)
(17, 18).
Data for some of the potential confounders of interest
(e.g., smoking, heart rate, race/ethnicity) were not available
from the administrative claims database. The bias analysis
demonstrated, however, that any unmeasured confounder
would have had to be strongly unbalanced between the
cohorts to have had a meaningful confounding effect.
Although the fixed-dose combination of PHEN/TPM
has been approved for chronic, long-term use, the av-
erage duration of use for current users was only
2.1 months. This figure was comparable with the aver-
age duration of use of PHEN (2.3 months) and TPM
(2.5 months). These durations of use were shorter than
those in the premarket clinical trials but presumably
reflect actual clinical patterns of use and might further
decrease any concerns about the risk of CV outcomes.
Conclusion
The present analysis of PHEN used concurrently with
TPM, either separately or in fixed-dose combination,
provides some reassurance about the absence of large
risks of CV outcomes caused by these agents as used in
clinical practice. We found a trend for a lower rate
of MACE and other CV outcomes among those with
current exposure to PHEN/TPM (including the fixed-
dose combination) than among the unexposed cohort.
However, considerable statistical uncertainty remains,
stemming from the small number of events, yielding 95%
CIs that ranged from strong negative associations to
small positive associations, with an upper 95% confi-
dence limit below a doubling of the rate for the composite
MACE outcome, during the relatively short time patients
were taking the medication.
Acknowledgments
Financial Support: The present study was conducted by RTI
Health Solutions, with funding from VIVUS, Inc.
Correspondence and Reprint Requests: Mary E. Ritchey,
PhD, RTI Health Solutions, 200 Park Offices Drive, P.O. Box
12194, Research Triangle Park, North Carolina 27709-2194.
E-mail: mritchey@rti.org.
Disclosure Summary: M.E.R., A.H., S.H., S.T., M.C-A.,
K.J.R., E.B.A., and M.S.A. are employees of RTI-HS, which
received funding from VIVUS, Inc. to conduct the present study.
The contract between RTI-HS and the sponsor, VIVUS, includes
independent publication rights. RTI is a nonprofit organization
that conducts work for government, public, and private orga-
nizations, including pharmaceutical companies. P.T.S. and
P.R.K. are ad hoc consultants for VIVUS, Inc. L.N. and C.P. are
employees and shareholders of VIVUS, Inc.
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Objective: Modest weight loss (5%-10%) is clinically meaningful in patients with overweight or obesity. However, greater weight loss may be required to achieve improvements in or remission of certain weight-related complications. Therefore, this study reviewed the effect of large weight loss (≥10%). Most studies reporting large weight loss and relevant outcomes used bariatric surgery or lifestyle modifications. Results: Benefits of large weight loss were observed in patients with various overweight- or obesity-related complications, including improvements in comorbidities such as type 2 diabetes and hypertension. Improvements in glucose metabolism and cardiovascular risk factors were observed in patients who achieved large weight loss through lifestyle interventions or pharmacotherapy (phentermine/topiramate 15/92 mg once daily or subcutaneous semaglutide 2.4 mg once weekly). Other benefits associated with large weight loss included reduced cancer risk and improvements in knee osteoarthritis, sleep apnea, fertility-related end points, and health-related quality of life. While costly, bariatric surgery is currently the most cost-effective intervention, although most weight-management programs are deemed cost-effective. Conclusions: Overall, large weight loss has a major beneficial impact on overweight- and obesity-related complications. Large weight loss should be the main treatment target when modest weight loss has had insufficient effects on obesity-related complications and for patients with severe obesity.
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More than 40% of adults in the United States suffer from obesity. Obesity is inextricably linked to many chronic illnesses like type‐2 diabetes mellitus, hypertension, hyperlipidemia, heart disease, sleep apnea, stroke, and cancers. When used in combination with lifestyle modifications, pharmacotherapy has a vital role in treating obesity and improves short‐term and long‐term outcomes. A growing number of physicians are now interested in obesity medicine, and many of them are seeking guidance on how to treat complex patients with co‐morbidities. This review provides a practical guide to the use of anti‐obesity medications across various obesity‐related comorbidities. It provides a general review of the currently approved anti‐obesity medications and effective combinations. It discusses the highlights of the major trials and recent studies assessing the benefits of anti‐obesity medications in comorbid conditions such as type‐2 diabetes mellitus , psychiatric disorders, cardiovascular diseases, hypertension, renal diseases, and liver diseases. This review briefly examines the aspects of recognizing and addressing iatrogenic weight gain; discusses the precautions and prescribing considerations of anti‐obesity medications, including side effects and possible dose adjustments in various comorbid conditions; and provides an expert opinion on an individualized choice of the best anti‐obesity medication.
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Introduction Obesity is associated with an increased risk of cardiovascular morbidity and mortality. Four medications are approved by the US Food and Drug Administration (FDA) for chronic weight management when used as an adjunct to a reduced-calorie diet and increased physical activity in adults. These medications result in clinically significant weight losses, as well as improvements in some cardiometabolic risk factors. Areas covered We briefly review the history of anti-obesity medications (AOMs) as related to cardiovascular safety, and summarize weight loss efficacy and cardiovascular data from clinical trials of orlistat, phentermine/topiramate, naltrexone/bupropion, and liraglutide. Expert opinion Current AOMs approved for chronic weight management have generally favorable effects on some cardiometabolic parameters. However, the long-term safety of orlistat, phentermine/topiramate, and naltrexone/bupropion on cardiovascular morbidity and mortality have not been established. The cardiovascular safety of liraglutide, at a dose of 1.8 mg/d, was demonstrated in a large randomized outcomes trial in participants with type 2 diabetes.
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The global pandemic of obesity and overweight now affects between 2.8 and 3.5 billion of the world population and shows no signs of abatement. Treatment for what is now recognized as a chronic disease includes pharmacotherapy, considered an essential component of comprehensive therapy. New drug discovery is robust, but the pace of the US Food and Drug Administration approval for obesity drugs has been glacial, and only a handful of approved drugs are available for treating obesity. In the last 20 years, the US Food and Drug Administration has and 223 endocrinologic drugs, but only 6 for obesity, 2 of which have been taken off market. Currently, there are only 9 drugs approved by the FDA for obesity treatment. US physicians have turned to off-label drug use in their effort to care for increasing numbers of patients with excess adiposity. Phentermine is the most commonly used drug for treating obesity. Although approved only for short-term use, US physicians have used it successfully for long-term since its initial approval in 1959. This drug, used off-label for long-term, has proven to be safe and effective, far safer than the disease it is used to treat. Phentermine and diethylpropion, an equally safe but somewhat less effective drug, are both generic and therefore inexpensive. These drugs have been maligned inappropriately because their two-dimensional structure diagrams resemble amphetamine and also because of unproven presumptions about their potential adverse effects. In the face of an increasing epidemic, worldwide obese and overweight patients deserve effective treatment that prescribing these drugs could provide, if rehabilitated and used more frequently. US physicians will likely continue to use any drug proven useful off-label for this illness until such time as more effective drugs are approved.
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Older-generation anticonvulsants that highly induce cytochrome P450 enzyme system activity produce metabolic abnormalities that may increase cardiovascular risk. The objective of this study was to evaluate the risk of ischemic cerebrovascular and coronary events in adult new users of anticonvulsants that highly induce cytochrome P450 activity compared with other anticonvulsant agents, as observed in a routine care setting. This was a cohort study of patients 40 to 64 years old from the HealthCore Integrated Research Database who had initiated an anticonvulsant medication between 2001 and 2006 and had no recorded major coronary or cerebrovascular condition in the 6 months before treatment initiation. Propensity score (PS) matching was used to evaluate ischemic cerebrovascular and coronary risk among anticonvulsant new users. High-dimensional propensity score (hdPS)-matched analyses were used to confirm adjusted findings. The study identified 913 events in 166 031 unmatched new treatment episodes with anticonvulsant drugs. In a PS-matched population of 22 864 treatment episodes, the rate ratio (RR) for ischemic coronary or cerebrovascular events associated with highly inducing agents versus other agents was 1.22 (95% CI, 0.90-1.65). The RR moved to 0.99 (95% CI, 0.73-1.33) with adjustment for hdPS matching (RR, 1.47; 95% CI, 0.95-2.28 for cerebrovascular events; RR, 0.70; 95% CI, 0.47-1.05 for coronary events). In this exploratory analysis, there was no evidence of a consistent and statistically significant effect of initiating anticonvulsants that highly induce cytochrome P450 activity on ischemic coronary or cerebrovascular outcomes compared with other agents, given routine care utilization patterns.
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A 56-week randomized controlled trial was conducted to evaluate safety and efficacy of a controlled-release combination of phentermine and topiramate (PHEN/TPM CR) for weight loss (WL) and metabolic improvements. Men and women with class II and III obesity (BMI ≥ 35 kg/m(2)) were randomized to placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg, added to a reduced-energy diet. Primary end points were percent WL and proportions of patients achieving 5% WL. Secondary end points included waist circumference (WC), systolic and diastolic blood pressure (BP), fasting glucose, and lipid measures. In the primary analysis (randomized patients with at least one postbaseline weight measurement who took at least one dose of assigned drug or placebo), patients in the placebo, 3.75/23, and 15/92 groups lost 1.6%, 5.1%, and 10.9% of baseline body weight (BW), respectively, at 56 weeks (P < 0.0001). In categorical analysis, 17.3% of placebo patients, 44.9% of 3.75/23 patients, and 66.7% of 15/92 patients, lost at least 5% of baseline BW at 56 weeks (P < 0.0001). The 15/92 group had significantly greater changes relative to placebo for WC, systolic and diastolic BP, fasting glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The most common adverse events were paresthesia, dry mouth, constipation, dysgeusia, and insomnia. Dropout rate from the study was 47.1% for placebo patients, 39.0% for 3.75/23 patients, and 33.6% of 15/92 patients. PHEN/TPM CR demonstrated dose-dependent effects on weight and metabolic variables in the direction expected to be beneficial with no evidence of serious adverse events induced by treatment.
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Obesity is associated with serious health risks. Monitoring obesity prevalence is relevant for public health programs that focus on reducing or preventing obesity. Between 2003–2004 and 2013–2014, there were no significant changes in childhood obesity prevalence, but adults showed an increasing trend. This report provides the most recent national estimates from 2015–2016 on obesity prevalence by sex, age, and race and Hispanic origin, and overall estimates from 1999–2000 through 2015–2016.
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The FDA is developing guidance on the use of “real-world evidence” — health care information from atypical sources, including electronic health records, billing databases, and product and disease registries — to assess the safety and effectiveness of drugs and devices.
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The age-specific relevance of blood pressure to cause-specific mortality is best assessed by collaborative meta-analysis of individual participant data from the separate prospective studies. Methods Information was obtained on each of one million adults with no previous vascular disease recorded at baseline in 61 prospective observational studies of blood pressure and mortality. During 12.7 million person-years at risk, there were about 56 000 vascular deaths (12 000 stroke, 34000 ischaemic heart disease [IHD], 10000 other vascular) and 66 000 other deaths at ages 40-89 years. Meta-analyses, involving "time-dependent" correction for regression dilution, related mortality during each decade of age at death to the estimated usual blood pressure at the start of that decade. Findings Within each decade of age at death, the proportional difference in the risk of vascular death associated with a given absolute difference in usual blood pressure is about the same down to at least 115 mm Hg usual systolic blood pressure (SBP) and 75 mm Hg usual diastolic blood pressure (DBP), below which there is little evidence. At ages 40-69 years, each difference of 20 mm Hg usual SBP (or, approximately equivalently, 10 mm Hg usual DBP) is associated with more than a twofold difference in the stroke death rate, and with twofold differences in the death rates from IHD and from other vascular causes. All of these proportional differences in vascular mortality are about half as extreme at ages 80-89 years as at,ages 40-49 years, but the annual absolute differences in risk are greater in old age. The age-specific associations are similar for men and women, and for cerebral haemorrhage and cerebral ischaemia. For predicting vascular mortality from a single blood pressure measurement, the average of SBP and DBP is slightly more informative than either alone, and pulse pressure is much less informative. Interpretation Throughout middle and old age, usual blood pressure is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg.
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Purpose Epilepsy is well known as a disorder in poststroke patients. However, studies that have investigated the association between epilepsy and the risk of subsequent stroke are limited. This population-based study investigated the incidence and risk of stroke in patients with epilepsy by using the Taiwan National Health Insurance claims data. Methods We identified 3812 patients newly diagnosed with epilepsy in 2000–2008 and 15 248 nonepilepsy comparisons frequency matched according to sex, age, and index year. We searched for subsequent stroke diagnoses in both cohorts until the end of 2009. The incidence rates and hazard ratios of stroke were estimated based on sex, age, the average defined daily doses (DDDs) of antiepilepsy drugs, and comorbidity. Results The stroke incidence of the epilepsy cohort was 3-fold higher than that of the comparison cohort. The age-specific results indicated that in the epilepsy cohort and the comparison cohort, the risk was the highest for the youngest group (20–39 y). Conclusion The patients with epilepsy exhibited a higher incidence of cerebral stroke than the general population did. In addition, younger patients with epilepsy and patients who took a high doses of antiepileptic drugs exhibited a high risk of stroke.
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Purpose: When using claims data, dichotomous covariates (C) are often assumed to be absent unless a claim for the condition is observed. When available historical data differs among subjects, investigators must choose between using all available historical data versus data from a fixed window to assess C. Our purpose was to compare estimation under these two approaches. Methods: We simulated cohorts of 20,000 subjects with dichotomous variables representing exposure (E), outcome (D), and a single time-invariant C, as well as varying availability of historical data. C was operationally defined under each paradigm and used to estimate the adjusted risk ratio of E on D via Mantel-Haenszel methods. Results: In the base case scenario, less bias and lower mean square error were observed using all available information compared with a fixed window; differences were magnified at higher modeled confounder strength. Upon introduction of an unmeasured covariate (F), the all-available approach remained less biased in most circumstances and rendered estimates that better approximated those that were adjusted for the true (modeled) value of C in all instances. Conclusions: In most instances considered, operationally defining time-invariant dichotomous C based on all available historical data, rather than on data observed over a commonly shared fixed historical window, results in less biased estimates.
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To validate an algorithm based upon International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes for acute myocardial infarction (AMI) documented within the Mini-Sentinel Distributed Database (MSDD). Using an ICD-9-CM-based algorithm (hospitalized patients with 410.x0 or 410.x1 in primary position), we identified a random sample of potential cases of AMI in 2009 from four Data Partners participating in the Mini-Sentinel Program. Cardiologist reviewers used information abstracted from hospital records to assess the likelihood of an AMI diagnosis based on criteria from the Joint European Society of Cardiology and American College of Cardiology Global Task Force. Positive predictive values (PPVs) of the ICD-9-based algorithm were calculated. Of the 153 potential cases of AMI identified, hospital records for 143 (93%) were retrieved and abstracted. Overall, the PPV was 86.0% (95% confidence interval; 79.2%, 91.2%). PPVs ranged from 76.3% to 94.3% across the four Data Partners. The overall PPV of potential AMI cases, as identified using an ICD-9-CM-based algorithm, may be acceptable for safety surveillance; however, PPVs do vary across Data Partners. This validation effort provides a contemporary estimate of the reliability of this algorithm for use in future surveillance efforts conducted using the Food and Drug Administration's MSDD. Copyright
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Obesity is a serious chronic disease. Controlled-release phentermine/topiramate (PHEN/TPM CR), as an adjunct to lifestyle modification, has previously shown significant weight loss compared with placebo in a 56-wk study in overweight and obese subjects with ≥2 weight-related comorbidities. This study evaluated the long-term efficacy and safety of PHEN/TPM CR in overweight and obese subjects with cardiometabolic disease. This was a placebo-controlled, double-blind, 52-wk extension study; volunteers at selected sites continued with original randomly assigned treatment [placebo, 7.5 mg phentermine/46 mg controlled-release topiramate (7.5/46), or 15 mg phentermine/92 mg controlled-release topiramate (15/92)] to complete a total of 108 wk. All subjects participated in a lifestyle-modification program. Of 866 eligible subjects, 676 (78%) elected to continue in the extension. Overall, 84.0% of subjects completed the study, with similar completion rates between treatment groups. At week 108, PHEN/TPM CR was associated with significant, sustained weight loss (intent-to-treat with last observation carried forward; P < 0.0001 compared with placebo); least-squares mean percentage changes from baseline in body weight were -1.8%, -9.3%, and -10.5% for placebo, 7.5/46, and 15/92, respectively. Significantly more PHEN/TPM CR-treated subjects at each dose achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared with placebo (P < 0.001). PHEN/TPM CR improved cardiovascular and metabolic variables and decreased rates of incident diabetes in comparison with placebo. PHEN/TPM CR was well tolerated over 108 wk, with reduced rates of adverse events occurring between weeks 56 and 108 compared with rates between weeks 0 and 56. PHEN/TPM CR in conjunction with lifestyle modification may provide a well-tolerated and effective option for the sustained treatment of obesity complicated by cardiometabolic disease. This trial was registered at clinicaltrials.gov as NCT00796367.