Context Research on factors that influence prescribing patterns and the extent
of change produced by clinical trial findings is limited.
Objective To examine the changes in prescribing of α-blockers for hypertension
treatment before and after the April 2000 publication of the unfavorable Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) early
termination involving the study's doxazosin mesylate arm. Changes in prescribing
were considered in the context of other potential concurrent influences on
medication use between 1996 and 2002, including changes in α-blocker
drug prices, generic conversion, drug promotion, and competition.
Design, Setting, and Patients Using 2 national pharmaceutical market research reports published by
IMS HEALTH, α-blocker prescription orders reported in the National Prescription Audit—a random computerized sample of about 20 000
of 29 000 retail, independent, and mail order pharmacies and mass merchandise
and discount houses—and office-based physician α-blocker prescribing
patterns reported in the National Disease and Therapeutic Index—a random
stratified sample of about 3500 physician offices—were tracked.
Outcome Measures Trends in physician-reported use of α-blockers and α-blocker
prescribing and dispensing by US pharmacies.
Results There were steady increases in α-blocker new prescriptions, dispensed
prescriptions, and physician drug use from 1996 through 1999. There was a
moderate reversal in these trends following ALLHAT early termination and subsequent
publications in early 2000. Between 1999 and 2002, new annual α-blocker
prescription orders declined by 26% (from 5.15 million to 3.79 million), dispensed
prescriptions by 22% (from 17.2 million to 13.4 million), and physician-reported
drug use by 54% (from 2.26 million to 1.03 million). Other potential influences
did not appear to have contributed significantly to this decline although
cessation of α-blocker marketing may have hastened the decline.
Conclusions Modest yet statistically significant declines in the use of doxazosin
and other α-blockers coincided with the early termination of the ALLHAT
doxazosin arm. Although physicians responded to this new evidence, strategies
to augment the impact of clinical trials on clinical practice are warranted.
Clinical trial results and practice guidelines are seen as the foundation
of evidence that should have primary influence over physician practice, including
patterns of medication prescribing. Past analyses, however, indicate limited
change in physician practice that have resulted from the publication of clinical
trial findings.1-3 Analysis
of results from randomized clinical trials of cardiovascular drug prescribing
patterns has suggested that more incentives are needed to effect change.4 Highlighting such factors as relative risk reduction,
numbers needed to treat, and increased quality of life may improve the impact
on physician prescribing behavior.5,6
Likewise, reports on the influence of practice guidelines on physician
behavior indicate that few studies show strong adherence to guidelines,7,8 whereas many studies suggest moderate
to high levels of nonadherence with recommendations.9-11 Reasons
cited for suboptimal adherence to guidelines include lack of resources or
awareness and physician disagreement with what constitutes best practice.12-15 A
variety of other factors also may influence medication prescribing practices.
Pharmaceutical promotion may have a direct influence on physician prescribing
prices and other characteristics of the pharmaceutical market also may determine
patterns of medication use.
α-Blocker use for the treatment of hypertension provides a pertinent
example for gauging the influence of clinical trial results and guidelines
on physician prescribing patterns in the context of other potential influences.
In spring 2000, significant changes in recommendations for α-blocker
use occurred as a result of early, unfavorable results from the Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). These
results indicated an increased risk associated with use of the α-blocker
doxazosin mesylate compared with diuretics.19 The
early termination results were widely disseminated in news releases and journal
publications.20,21 With 50 million
individuals in the United States diagnosed as having hypertension incurring
annual treatment costs of $15.5 billion,22 these
early ALLHAT results would be expected to have had broad implications on prescribing
Using nationally representative data available from IMS HEALTH, we tracked
trends in α-blocker prescriptions filled by retail pharmacies and reports
of α-blocker use in patient encounters with office-based physicians.
We considered the impact of the early ALLHAT results and subsequent clinical
recommendations in the context of other potentially influential factors, including
drug promotional efforts, variations in drug price, generic conversion of α-blockers,
and market competition.
Our analytic goals were 2-fold: to describe patterns of α-blocker
use before and after the April 2000 publication of the early ALLHAT results
and to examine whether these clinical trial results or alternative influences
were associated with changes in α-blocker prescribing that occurred
in this time frame.
Patterns of α-Blocker Use
Our analysis focused on the traditional unselective α-blockers
(Universal System of Classification [USC] code 31440) doxazosin (Cardura),
terazosin hydrochloride (Hytrin), and prazosin hydrochloride (Minipress).
These medications function as antihypertensives by blocking action against α1-receptors that mediate the constriction of blood vessels through increased
smooth muscle tone. We also separately considered the use of the non-antihypertensive,
selective α-blocker tamsulosin hydrochloride (Flomax) (within USC code
24200). Like traditional α-blockers, tamsulosin is used to treat benign
prostatic hyperplasia and could have been substituted for traditional α-blockers.
Data tracking the use of α-blockers were obtained from 2 data
reports published by IMS HEALTH, an independent pharmaceutical market research
company in Plymouth Meeting, Pa. Information was obtained on patient visits
to office physicians from the National Disease and Therapeutic Index (NDTI)
and on retail pharmacy activity from the National Prescription Audit Plus (NPA).
Retail Pharmacy Prescribing and Dispensing of Medication. The NPA consists of a national, random, computerized sample of approximately
20 000 of a total of 29 000 retail pharmacies, independent pharmacies,
mass merchandise and discount houses, and mail order pharmacies. The universe
of 29 000 stores sampled in the IMS HEALTH database accounts for more
than half of all retail pharmacies in the United States. The sample is resized
on a semiannual basis. Although pharmacy data are collected every day, we
used data reported in monthly aggregates, with the major unit of measure being
the prescription. Prescription data consist of 2 types: prescription orders
received by pharmacies and actual medications dispensed by pharmacies and
received by consumers.
The NPA Therapeutic Category Report shows monthly national data on both
the inflow of prescriptions written by physicians and the retail outflow of
filled prescriptions moving from pharmacies to consumers. For each dose of
each brand and generic drug name, data are reported on the number of prescriptions,
the number of new and refill dispensed prescriptions, total dollar charges
of all dispensed prescriptions, and drug manufacturer. New prescriptions are
those ordered by physicians; most commonly the written physical orders are
received by pharmacies to be processed and then dispensed to patients. We
tracked quarterly national prescribing and dispensing patterns for α-blockers
at retail pharmacies from 1996 through 2002, following individual trends for
brand name and generic versions of doxazosin, prazosin, and terazosin.
We identified the number of both new prescriptions and total dispensed
prescriptions as the likely best indicators of physicians' attitudes toward
the use of α-blockers. In contrast, the dispensing of refills reflects
the accumulation of current and past prescribing practices. Because drug use
reported by office physicians indicates the medications that were newly prescribed
or continued at the conclusion of a visit, decreasing drug use would suggest
physician decisions to discontinue α-blocker use.
Prescribing by Office-Based Physicians. The
NDTI is a continuing survey of a random stratified sample of approximately
3500 office-based physicians in the United States that is subject to attrition
with replacement. It provides nationally representative information on drug
use patterns for patients treated by office-based physicians. The surveyed
physicians were selected by random stratified sampling by specialty using
master lists of the American Medical Association and the American Osteopathic
Association (both in Chicago, Ill). Participating physicians were surveyed
for 2 consecutive workdays per quarter and provided information on each patient
encounter during this period. Physician contact with patients largely consists
of office visits although encounters with patients during telephone calls
and hospital and nursing home visits also are included. The participation
rate among physicians for reporting their prescribing patterns was at 84%
in 1998, which was similar for other years. Physicians report information
on diagnoses for each patient and then report all new or continuing drugs
for each diagnosis. The NDTI does not capture patient adherence to medications
and reflects a physician's best knowledge of medications taken by the patient.
In NDTI, each reported use of a drug constitutes a drug use. Both brand and
generic names are recorded in the survey. We used quarterly prescribing data
from 1996 through 2002 to assess the likelihood that α-blockers were
mentioned during office visits by patients reported to have hypertension.
Potential Influences on α-Blocker Use
ALLHAT Publication. ALLHAT was a large-scale,
9-year randomized clinical trial conducted from February 1994 to March 2002.23 One of its goals was to evaluate the possible superiority
of α-blockers, calcium channel blockers, and angiotensin-converting
enzyme (ACE) inhibitors over less expensive, generic diuretics in lowering
blood pressure and preventing coronary heart disease and other cardiovascular
events in high-risk hypertensive persons 55 years and older.24 In
January 2000, a decision was made to terminate the doxazosin arm of the ALLHAT
study after finding that the risk of combined cardiovascular events with the α-blocker
doxazosin was more than 25% higher than that among patients treated with chlorthalidone,
a thiazide diuretic.25 The doxazosin arm findings
were reported in a press release issued by the National Heart, Lung, and Blood
Institute in March 2000, followed by publication in JAMA on April 15, 2000.
Although we concern ourselves herein with the early α-blocker ALLHAT
results, final results that suggest modestly superior outcomes with use of
chlorthalidone over lisinopril and amlodipine were published in JAMA on
December 18, 2002.22
National Recommendations and Guidelines. In
March 2000, following the ALLHAT early termination, clinical recommendations
were released suggesting that α-blockers may not be the best choice
for initial therapy of hypertension.20 Previous
Joint National Committee (JNC V) guidelines in 1993 had suggested the initial
use of diuretics and β-blockers but with possible consideration of α-blockers,
calcium channel blockers, and ACE inhibitors as other first-line agents.26 In 1997, JNC VI guidelines emphasized the use of
diuretics and β-blockers over α-blockers and other medications
except as dictated by compelling comorbidities.27
Drug Prices. The NPA retail pharmacy data provide
total drug prices for antihypertensive medications. The mean retail drug cost
per prescription was derived by dividing total dollar cost to pharmacies by
the total number of prescriptions dispensed. We specifically followed drug
prices per prescription from 1996 through 2002 for individual α-blocker
drugs. We examined temporal fluctuations in drug prices of α-blockers
in relation to prescribing patterns to gauge their potential influence on
physician choices in drug prescribing.
Drug Promotion. The IMS HEALTH Office Promotion
Report (OPR) is an ongoing survey of a national sample of approximately 3862
US office-based physicians. Survey participants are chosen from a random stratified
sample of physicians from across 25 specialties in 43 states. The OPR data
are reported in monthly aggregates and are stratified by pharmaceutical company,
medication class, and drug name.
The OPR provides information on physician contact with pharmaceutical
sales representatives, including estimates of corporate expenditures in promotional
activities related to individual products by these sales representatives.
The dollar value is derived by multiplying the reported minutes of detailing
associated with each product by a current average cost per minute estimate.
We examined quarterly total dollar expenditure for α-blocker office
promotion from 1996 through 2002 to monitor trends in drug promotion.
Other Market Factors. Other commercial factors
were explored as possible influences on physician prescribing behavior. The
most notable market event affecting α-blockers occurred when generic
doxazosin became available in October 2000. Prazosin had been available as
a generic in September 1988 and terazosin in March 1998.
We also considered patterns of α-blocker use for the treatment
of indications other than hypertension, particularly benign prostatic hyperplasia.
In examining the use of tamsulosin in the treatment of benign prostatic hyperplasia,
we found that increases in tamsulosin use predated the decline in traditional α-blocker
use. Furthermore, the use of traditional α-blockers for genitourinary
disorders increased slightly from 40% in 1996 to 42% in 2002, suggesting that
any decline in α-blocker use could not be attributed to direct substitution
by tamsulosin. We have not presented further details of this analysis.
Finally, we also considered broader trends in antihypertensive medication
prescribing to gauge whether α-blockers may have been subject to increasing
competition from other drugs in 2000. We present information on changes in
the use of other drug classes, as well as individual medications.
Statistical Analysis of NPA and NDTI Data
The Cox and Stuart test for trend was used to test for significance
in changes observed for α-blocker prescribing patterns over time.28 We analyzed the temporal sequence of NPA prescribing
and dispensing data and applied a 1-tailed test. The null hypothesis states
that there was no significant downward trend in α-blocker use. We used
Microsoft Office Excel (Redmond, Wash) software to statistically analyze the
IMS Health data reported herein. Results were evaluated with P = .05 as the threshold for statistical significance. Estimated sampling
errors also were available for both NPA29 and
NDTI data,30 and we used them to derive 95%
confidence intervals (CIs) for our reported estimates.
Before the publication of the ALLHAT doxazosin results, overall α-blocker
use slowly increased according to each available data source. As described
herein, between 1996 and 1999 the observed increase ranged from 5% to 15%,
depending on the metric used to assess prescribing patterns. Following the
ALLHAT results, α-blocker use declined by as much as 54% from 1999 through
2002. In addition to the impact of the early ALLHAT results, we also considered
other potential influences, including drug promotional efforts, drug prices,
generic conversion of α-blockers, and market competition. With the possible
exception of diminished promotional efforts, these other factors do not appear
to have contributed significantly to the observed decline in α-blocker
Trends in New and Refill α-Blockers Dispensed by Pharmacists
US retail pharmacies dispensed 3.53 million (95% CI, 3.52 million to
3.54 million) α-blocker prescriptions to consumers in the first quarter
of 1996; the total dispensing volume increased consistently through 1999 to
peak at 4.44 million (95% CI, 4.43 million to 4.45 million) in the fourth
quarter of 1999 (Figure 1). Following
early ALLHAT termination, this increasing trend reversed beginning in the
first quarter of 2000 (4.21 million; 95% CI, 4.20 million to 4.22 million)
and declined continuously thereafter to 3.46 million (95% CI, 3.45 million
to 3.47 million) in the first quarter of 2002 and to 3.26 million (95% CI,
3.25 million to 3.27 million) by the fourth quarter of 2002. The trends observed
for total dispensed prescriptions include both newly dispensed and refills
for α-blockers. The downward trend recorded for total dispensed α-blockers
was statistically significant (P = .006) using the
Cox and Stuart test for trend. The quantity of newly dispensed α-blocker
prescriptions increased by 16% from 1.16 million (95% CI, 1.15 million to
1.17 million) in the first quarter of 1996 to 1.35 million (95% CI, 1.34 million
to 1.36 million) in the fourth quarter of 1999. By the second quarter of 2000,
it declined by 8% to 1.23 million (95% CI, 1.22 million to 1.24 million).
Newly dispensed prescriptions declined further to 0.91 million (95% CI, 0.90
million to 0.92 million) in the fourth quarter of 2002, marking a 33% decline
from 1999 levels. The decline in newly dispensed α-blockers was also
measured to be statistically significant (P = .006).
Dispensed refill values likewise show a statistically significant decline
in the α-blocker trend line (P = .03). Following
a similar trend, the number of dispensed refill α-blockers increased
by 30% from 2.37 million (95% CI, 2.36 million to 2.38 million) in the first
quarter of 1996 to 3.09 million (95% CI, 3.08 million to 3.10 million) in
the fourth quarter of 1999. Values decreased by 24% from peak 1999 levels
to 2.35 million (95% CI, 2.34 million to 2.36 million) in the fourth quarter
of 2002. On an annual basis, dispensing grew from 15.0 million in 1996 to
17.2 million in 1999 before declining by 22% to 13.4 million in 2002. Note
that the volume of total dispensed prescriptions exceeds the number of prescriptions
received by pharmacies because of dispensing that occurs as previously received
prescriptions are refilled.
The dispensing of generic and brand name prazosin remained relatively
infrequent and in steady decline from 1996 through 2002. Despite an early
increase in 1996, brand name terazosin declined continuously throughout the
entire study span, a 15% decrease between the fourth quarter of 1996 and the
second quarter of 1999 and an overall 85% decrease by the fourth quarter of
2002. Dispensed brand name doxazosin increased from 1.1 million (95% CI, 1.09
million to 1.11 million) in the first quarter of 1996 to 2.28 million (95%
CI, 2.27 million to 2.29 million) in the fourth quarter of 1999, slightly
declined from the first quarter of 2000 (2.21 million; 95% CI, 2.20 million
to 2.22 million) to the third quarter of 2000 (2.17 million; 95% CI, 2.16
million to 2.18 million) but then decreased significantly to 0.67 million
(95% CI, 0.66 million to 0.68 million) in the first quarter of 2001 and to
0.16 million (95% CI, 0.15 million to 0.17 million) in the fourth quarter
Trends in Newly Prescribed α-Blockers (NPA)
The estimated number of α-blocker new prescription orders received
by pharmacies increased by 16% from 1.16 million (95% CI, 1.11 million to
1.21 million) prescriptions in the first quarter of 1996 to a peak of 1.35
million (95% CI, 1.31 million to 1.39 million) in the fourth quarter of 1999
(Figure 2). α-Blocker prescriptions
then decreased to 1.15 million (95% CI, 1.11 million to 1.19 million) by the
third quarter of 2000, with a further decline to 0.91 million (95% CI, 0.87
million to 0.95 million) by the end of 2002, reflecting a 33% decline from
peak 1999 levels. On an annual basis, new α-blocker prescriptions increased
from 4.90 million in 1996 to 5.15 million in 1999 before declining by 26%
to 3.79 million in 2002. Statistical analysis using the Cox and Stuart test
for trend showed a significant downward trend for newly prescribed α-blockers
after the ALLHAT results (P = .006). The decline
in total α-blocker use resulted mostly from overall decreased prescriptions
of both brand name and generic doxazosin from 0.70 million (95% CI, 0.67 million
to 0.73 million) in the first quarter of 2000 to 0.49 million (95% CI, 0.46
million to 0.52 million) in the fourth quarter of 2002. There was a transient
increase in total doxazosin prescriptions between the third quarter of 2000
(0.62 million; 95% CI, 0.59 million to 0.65 million) and the fourth quarter
of 2000 (0.76 million; 95% CI, 0.73 million to 0.79 million) that accompanied
the availability of generic doxazosin (Figure
Generic Conversion of Doxazosin
Transition from brand name to generic doxazosin occurred in October
2000, only 6 months after the publication of the ALLHAT results. As noted,
brand name doxazosin dispensing decreased by 86% from 2.17 million (95% CI,
2.16 million to 2.18 million) in the third quarter of 2000 to 0.30 million
(95% CI, 0.30 million to 0.30 million) in the fourth quarter of 2001 following
the availability of generic doxazosin (Figure
3). The availability of less expensive generic doxazosin (priced
at $29 per prescription in the fourth quarter of 2001 vs $41 for brand name
doxazosin), however, offset much of this decline. Generic doxazosin dispensed
was 1.71 million in the fourth quarter of 2001 so that the net reduction in
total doxazosin dispensing (generic plus brand name) was consistent with trends
established early in 2000 before doxazosin's generic conversion.
α-Blocker Use Reported by Office Physicians (NDTI)
Annual α-blocker drug use at visits to office-based physicians
in the NDTI increased by 9% from 2.08 million (95% CI, 1.70 million to 2.46
million) in 1996 to 2.26 million (95% CI, 1.89 million to 2.63 million) in
1999. During this time, the proportion of drug use associated with the treatment
of hypertension and related cardiovascular disease remained stable at 58%.
As a result, α-blocker use for hypertension treatment increased from
1.20 million (95% CI, 0.93 million to 2.47 million) in 1996 to 1.28 million
(95% CI, 1.02 million to 1.54 million) in 1999. Following the ALLHAT doxazosin
results, quarterly α-blocker drug use declined from 0.52 million (95%
CI, 0.37 million to 0.67 million) in the fourth quarter of 1999 to 0.42 million
(95% CI, 0.29 million to 0.55 million) in the fourth quarter of 2000, then
gradually declined further to 0.22 million (95% CI, 0.13 million to 0.31 million)
by the fourth quarter of 2002 (Figure 4).
Overall, annual α-blocker use declined by 54% between 1999 (2.26 million;
95% CI, 1.89 million to 2.63 million) and 2002 (1.03 million; 95% CI, 0.79
million to 1.27 million). α-Blocker use for hypertension decreased by
66% from 0.32 million (95% CI, 0.21 million to 0.43 million) in the fourth
quarter of 1999 to 0.11 million (95% CI, 0.05 million to 0.17 million) in
the fourth quarter of 2002.
Office Promotion Expenditures
Estimated expenditures for the office promotion of α-blockers
increased by 47% from $6.3 million in the first quarter of 1996 to a peak
of $9.3 million in the third quarter of 1998 (Figure 5). Following this peak, there was a slow decline in promotional
expenditures to $7.3 million in the third quarter of 1999. Office promotion
expenditure then declined more rapidly to $5.5 million in the first quarter
of 2000 and $4.0 million in the third quarter of 2000. By the first quarter
of 2001, no α-blockers were being promoted on the market. Office promotion
expenditures for brand name doxazosin initially increased from $3.0 million
in the first quarter of 1996 to a peak of $5.5 million in the second quarter
of 2000 followed by a rapid decline to no expenditures by the first quarter
Trends in α-Blocker Drug Price per Prescription
Trends in drug prices were evaluated to gauge whether observed trends
in α-blocker use were consistent with price-driven market responses.
The mean price per α-blocker prescription increased from $41 in 1996
to $45 in 2000 before decreasing to $40 in 2002. This pattern reflects 2 countervailing
trends in the consistently increasing prices of brand name α-blockers
and in the availability of lower-priced generic forms of terazosin in March
1998 and doxazosin in October 2000. Without these generic conversions, overall
drug prices would have continued to increase in 2001 and 2002. For example,
the price per prescription of brand name terazosin increased 77% from $48
in the first quarter of 1996 to $85 in the fourth quarter of 2002, whereas
brand name doxazosin increased 29% from $34 in the first quarter of 1996 to
$44 in the fourth quarter of 2002. These rates of increase in the price of
brand name products were substantially in excess of the increase in the overall
producer price index for pharmaceuticals, the medical consumer price index,
or overall inflation in the US economy. Lower prices were associated with
generic terazosin ($52 in 2002) and generic doxazosin ($28 in 2002). The ratio
of brand name to generic prices therefore increased over time for both terazosin
(1.15 in 1999 to 1.60 in 2002) and doxazosin (1.23 in 2000 to 1.54 in 2002)
as a result of increasing brand name prices and small decreases in generic
Trends in Other Classes of Antihypertensive Drugs
We examined whether the decline in α-blocker use corresponded
to the growth in one or more drug classes or individual drugs. This analysis
suggested that angiotensin receptor blockers (ARBs) might have partially replaced α-blockers
even though ARBs experienced substantial growth before the decline in α-blocker
use. Between 1996 and 2002, the use of ARBs rose steadily from 3% of patients
with hypertension in 1996 to 18% by 2002, with the largest increases between
1999 (8.5%) and 2000 (14.0%). Among ARBs, valsartan use gradually increased
from 0% in 1996 to 7% in 2002, whereas losartan potassium use increased from
3% in 1996 to 6% in 2002. The use of ACE inhibitors gradually increased from
33% among patients with hypertension in 1996 to 40% in 2002, without any differences
in this pattern before and after the first quarter of 2000. Lisinopril, the
ACE inhibitor studied in ALLHAT, did not increase substantially between 1996
(12%) and 2002 (13%). The use of benazepril increased from 4% in 1996 to 8%
in 2002 (including its use as a combination product with amlodipine). Overall,
calcium channel blocker use declined from 34% in 1996 to 26% in 2002. However,
amlodipine, the calcium channel blocker studied in ALLHAT, increased from
9% in 1996 to 17% in 2002, with the greatest increase between 2000 (12%) and
2001 (16%). Diuretic use declined slightly from 22% of patients in 1996 to
19% in 2002. Although use of chlorthalidone, the diuretic studied in ALLHAT,
remained rare (<1% of patients), hydrochlorothiazide use increased slightly
from 6% in 1996 to 8% in 2002. β-Blocker use remained essentially stable
at 19.0% among patients with hypertension between 1996 and 2002, as did the
use of the leading β-blocker atenolol (9% in 2002). Note that more than
1 antihypertensive medication may be reported per patient because of the use
of combination products and multiple antihypertensive products.
Our study describes α-blocker prescribing patterns before and
after the publication of early ALLHAT results in April 2000 and examines other
possible simultaneous influences on physician prescribing patterns for α-blockers
during this period. The doxazosin arm of the ALLHAT trial was discontinued
in January 2000, with the subsequent release of clinical recommendations against
the use of α-blockers as first-line agents for hypertension treatment.
Our description of patterns in α-blocker use immediately before
and after the publication of the early ALLHAT results suggests a reversal
of preexisting trends. Before the ALLHAT early termination results were released, α-blocker
prescribing and dispensing increased steadily between the first quarter of
1996 through the fourth quarter of 1999. Beginning in the second quarter of
2000, synchronous with the ALLHAT results, overall α-blocker drug use
began to decline. We noted consistent patterns for newly written prescriptions,
prescriptions dispensed by pharmacies, and drug use patterns reported by office
physicians. The most significant declines were noted in drug use patterns,
perhaps suggesting that visits to physicians provided an opportunity to discontinue
the use of α-blockers that had been previously prescribed.
We examined the declining trends in α-blocker use in the context
of other influential factors, including generic conversion of doxazosin, drug
promotion, drug prices, and other market factors. Among these factors, significant
reduction in promotion coincides with decline in α-blocker use although
the most significant declines in promotion occurred after α-blocker
use had begun to decline. The complexity and variety of these potential influences,
however, make definitive inference difficult.
Beyond the ALLHAT early termination results, generic conversion of brand
name doxazosin may have temporarily delayed the decline in α-blocker
use. An increase in α-blocker prescriptions was noted between the fourth
quarter of 2000 and the first quarter of 2001, marking an increase in α-blocker
use, according to this metric, in the otherwise decreasing trend line. The
decrease in total α-blocker prescriptions following early ALLHAT results
preceded any significant decline in doxazosin promotion expenditures. Brand
name doxazosin promotion expenditures decreased in the fourth quarter of 2000.
This pattern is consistent with past economic studies31 that
link declines in promotional expenditures to impending loss of patent status.
The sharp decline in doxazosin promotion may have further exacerbated the
decrease in α-blocker use observed from mid 2000 to 2002. The ratio
of prices for brand name doxazosin to generic increased over time after the
initial availability of generic doxazosin. This pattern of price change is
consistent with that described in economic studies of generic entry and pricing.32 The α-blocker prescription rates also declined
despite the availability of less expensive generic versions between 2000 and
2002. In contrast, the average price per prescription for all antihypertensive
medications increased from $43.85 in 1993 to $44.83 in 2001. To the extent
that prescribing is sensitive to such comparative prices, the reduced cost
of selected generic α-blockers could have offset what might have been
an even faster decline in their use.33,34
Increased market competition from other antihypertensive drugs, particularly
ARBs, also may have influenced the prescribing of α-blockers. Angiotensin
receptor blockers, as well as ACE inhibitors and the calcium channel blocker
amlodipine, gained market share contemporaneously with the decline in α-blocker
use. As a relatively novel addition to the antihypertensive market, ARBs may
have been a leading candidate for competitive substitution. Despite the inverse
association between ARB use and α-blocker use, however, our data does
not allow assessment of whether patients were switched from one drug to another.
Past literature suggests that physician response to clinical recommendations
is more rapid when clinical trials reveal negative rather than positive results.35 Although our findings are consistent with past studies,
physician response was neither as marked nor as rapid as might have been expected.
Several limitations of our analysis should be highlighted. The NDTI
data are based on a sample of physicians who may not necessarily be representative
of all physicians. These physicians report their best knowledge of patients'
medications during a sample of visits. Although a large sample of retail pharmacies
is available in NPA, we did not analyze information on drug dispensing from
other sources. These limitations are mitigated by the cross-validation provided
by using both NDTI and NPA data. The comparable trends we observed across
these 2 databases argue for the validity of the prescribing patterns recorded
in this study. This study builds on previous research on individual factors
that affect physician prescribing decisions. There is an absence of research
focusing on multiple, simultaneous influences on national prescribing patterns.
Despite our consideration of multiple factors in this study, we acknowledge
that all conceivable factors potentially affecting drug prescribing have not
been included. In addition, all of the complex interactions between these
factors have not been explicitly considered in this descriptive analysis.
Because there are multiple simultaneous influences, it is difficult
to establish a primary influencing factor on the significant decline in physician
prescribing of α-blockers. Nevertheless, our findings are clearly consistent
with ALLHAT early termination results having a significant impact on α-blocker
use. Declining pharmaceutical industry promotion also may have contributed
further to decreased α-blocker use. The lack of an abrupt and more pronounced
decline in prescribing shortly after the ALLHAT results, however, suggests
slow and potentially incomplete diffusion of information from this clinical
trial. Combined with past work that questions the potency of clinical trial
results on physician practice, our analysis suggests the need for additional
strategies to augment the dissemination of results from clinical trials.
Dunn DR. Dissemination of the published results of an important clinical trial:
an analysis of the citing literature. Bull Med Libr Assoc.1981;69:301-306.
Collins R, Julian D. British Heart Foundation surveys (1987 and 1989) of United Kingdom
treatment policies for acute myocardial infarction. Br Heart J.1991;66:250-255.
Friedman L, Wenger NK, Knatterud GL. Impact of the Coronary Drug Project findings on clinical practice. Control Clin Trials.1983;4:513-522.
Reiffel JA, Cook JR. Physician attitudes toward the use of type IC antiarrhythmics after
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