ORIGINAL RESEARCH & REVIEWS

EPIDEMIOLOGY & RISK FACTORS

Retrospective Observational Real-World Outcome Study to

Evaluate Safety Among Patients With Erectile Dysfunction (ED) With
Co-Possession of Tadalafil and Anti-Hypertensive Medications
(anti-HTN)
Anthony P. Nunes, PhD,1 John D. Seeger, PharmD, DrPH,1 Andrew Stewart, MPH,2 Alankar Gupta, MD, MS, MBA,2 and
Thomas McGraw, PhD2

ABSTRACT

Background: Erectile dysfunction (ED) is a common condition affecting male adults and may be associated with
hypertension, diabetes, hyperlipidemia, and obesity. Phosphodiesterase type 5 (PDE5) inhibitors, such as tadala-
fil, are the first-line drug therapy for ED. Studies and the current prescribing information of these PDE5 inhibi-
tors indicate they are mechanistic mild vasodilators and, as such, concomitant use of a PDE5 inhibitor with anti-
hypertensive medication may lead to drops in blood pressure due to possible drug-drug interaction.
Aim: Evaluate risks of hypotensive/cardiovascular outcomes in a large cohort of patients with ED that have co-
possession of prescriptions for tadalafil and hypertensive medications versus either medication/s alone.
Methods: A cohort study conducted within an electronic health record database (Optum) representing hospitals
across the US. Adult male patients prescribed tadalafil and/or anti-hypertensive medications from January 2012
to December 2017 were eligible. Possession periods were defined by the time patients likely had possession of
medication, with propensity score-matched groups used for comparison.
Outcomes: Risk of hypotensive/cardiovascular outcomes were measured using diagnostic codes and NLP algo-
rithms during possession periods of tadalafil + anti-hypertensive versus either medication/s alone.
Results: In total there were 127,849 tadalafil + anti-hypertensive medication possession periods, 821,359 anti-
hypertensive only medication possession periods, and 98,638 tadalafil only medication possession periods during
the study; 126,120 were successfully matched. Adjusted-matched incidence rate ratios (IRRs) for the anti-hyper-
tensive only possession periods compared with tadalafil + anti-hypertensive periods of diagnosed outcomes were
all below 1. Two outcomes had a 95% confidence interval (CI) that did not include 1.0: ventricular arrhythmia
(IRR 0.79; 95% CI 0.66, 0.94) and diagnosis of hypotension (IRR 0.79; 95% CI 0.71, 0.89).
Clinical Implications: Provides real world evidence that co-possession of tadalafil and anti-hypertensive medica-
tions does not increase risk of hypotensive/cardiovascular outcomes beyond that observed for patients in posses-
sion of anti-hypertensive medications only.
Strengths and Limitations: EHR data are valuable for the evaluation of real world outcomes, however, the
data are retrospective and collected for clinical patient management rather than research. Prescription data repre-
sent the intent of the prescriber and not use by the patient. Residual bias cannot be ruled out, despite propensity
score matching, due to unobserved patient characteristics and severity that are not fully reflected in the EHR
database.
Conclusion: In the studied real world patients, this study did not demonstrate an increased risk of hypotensive or
cardiovascular outcomes associated with co-possession of tadalafil and anti-hypertensive medications beyond that
observed for patients in possession of anti-hypertensive medications only.

Received June 4, 2021. Accepted October 9, 2021.
1
Optum, Optum Life Sciences, Waltham, MA, USA;
2
Consumer Healthcare Medical Affairs, Sanofi, Bridgewater, NJ, USA
Copyright © 2021 The Authors. Published by Elsevier Inc. on behalf of the
International Society for Sexual Medicine. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
https://doi.org/10.1016/j.jsxm.2021.10.012

74 J Sex Med 2022;19:74−82

Tadalafil With Antihypertensive Medications 75

Nunes AP, Seeger JD, Stewart A, et al., Retrospective Observational Real-World Outcome Study to Evalu-
ate Safety Among Patients With Erectile Dysfunction (ED) With Co-Possession of Tadalafil and Anti-
Hypertensive Medications (anti-HTN). J Sex Med 2022;19:74−82.
Copyright © 2021 The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual
Medicine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
Key Words: Tadalafil; Erectile Dysfunction; Cardiovascular Diseases; Hypertension

INTRODUCTION
Erectile dysfunction (ED) is a common condition affecting
the adult male population. Prevalence in the US male population
≥20 years is 18.4%; increasing from 5.1% in men 20−39 years
to 70.2% in men ≥70 years.1 Hypertension remains the leading
cause of death globally, accounting for 10.4 million deaths per
year,2 with nearly half of US adults having a hypertension diag-
nosis or hypertension treatment.3 Both hypertension and ED are
usually caused by endothelial dysfunctions and/or dysregulation
of vascular and cavernous smooth muscles.4 Evidence suggests
that there is a pathophysiological overlap between those with car-
diovascular disease and those with ED, and those with ED and
risk for future cardiovascular disease.4
Many studies have described ED preceding the onset of coro-
nary artery disease and sharing common risk factors (age, diabetes,
smoking, hypercholesterolemia, hypertension).5−9 Analysis of data
from the Prostate Cancer Prevention Trial evaluated the associa-
tion of ED with cardiovascular disease and found that of those
without CVD, 47% of men had ED at study entry and 57%
developed ED within 5 years, and that there was a strong associa-
tion between ED and later development of cardiovascular events
in these patients.10 In addition, studies have shown that hyperten-
sion is common among men with ED; up to 41.6%.11 Further-
more, men with ED may be up to 38.3% more likely to have
hypertension than those without according to a 2-cohort retro-
spective RWE study conducted over 6 years.12 Men treated for
hypertension are more likely to have ED than those who remain
untreated, and this issue is under-recognized and under-treated.13
Current US guidelines for the treatment of hypertension recom-
mend thiazide diuretics, calcium channel blockers and angiotensin-
converting enzyme inhibitors or angiotensin-receptor blockers as
first line therapy.14 ED may be an adverse effect of certain classes of
anti-hypertensive treatments such as thiazide diuretics and beta-
blockers that is not directly addressed in most guidelines.14,15
Following lifestyle modification, phosphodiesterase type 5
(PDE5) inhibitors are the first-line therapy indicated for the treat-
ment of ED. PDE5 inhibitors are contraindicated with patients
taking organic nitrates and riociguat due to risk of hypertension,
and with the use of alpha-blockers they are cautioned due to the
possible risk of additive hypotension effect.16,17 PDE5 inhibitors
may cause a small transient drop in blood pressure in healthy men,
and controlled drug-drug interaction studies have suggested that
concomitant use of a PDE5 inhibitor with some anti-hypertensive
medication may lead to no or small additive drops in blood pres-
sure.16 While not contraindicated for stable hypertensive patients,
most PDE5 prescribing information guides physicians to consider
the relative cardiovascular health of patients prior to co-prescrip-
tion, and to discuss with patients the potential blood pressure-low-
ering effect. It is unclear whether the small blood pressure-lowering
effects observed with co-possession of PDE5 inhibitors and anti-
hypertensive medications in clinical trials will translate to meaning-
ful effects in the real world, or result in significant risks of clinically
identifiable outcomes.
This study used a large US electronic health record (EHR)
database to evaluate the risk of hypotensive or cardiovascular out-
comes among patients with ED who had co-possession of pre-
scriptions for tadalafil (a PDE5 inhibitor) and anti-hypertensive
medication compared to those who had either component alone.
METHODS
Data Source
Data were derived from a large US-based electronic medical
record database, Optum’s EHR Research Database. The database
contains patient-level data from multiple electronic medical record
systems sourced from more than 46 provider networks representing
more than 92,000 providers and 195 hospitals across the US. The
electronic medical records are mapped to a common EHR data
structure and include structured fields for coded medical diagnoses,
drug prescriptions, laboratory results and practice management data
from both ambulatory and inpatient settings. Also included are
unstructured free-text information from clinical notes relating to
medical encounters. This information has been extracted into a
semi-structured data table using a generalized natural language proc-
essing (NLP) system.18,19 The separate electronic medical record
systems are mapped to a common EHR data structure.
Study Participants and Design
Adult male patients aged >18 years who were prescribed tada-
lafil and/or anti-hypertensive medications between January 1,

J Sex Med 2022;19:74−82

76
2012 and December 30, 2017, and with 1 year of encounter
data, were identified in the EHR database. Tadalafil and anti-
hypertensive medication prescriptions were identified from struc-
tured data fields corresponding to written prescriptions and med-
ication orders. All doses of tadalafil were included in this
assessment: 5mg, 10mg or 20 mg on-demand and 5mg daily.
National drug codes (NDC) are not consistently recorded in the
EHR systems; NDC codes were used where available and drug
names mapped to NDC codes where they were not. Patient pos-
session periods describing prescription of alpha-blockers or
nitrates for anti-hypertensive therapy were excluded from the
analysis.
The date of cohort entry was determined by the first prescrip-
tion for tadalafil and/or anti-hypertensive medication meeting all
additional criteria: ≥1 year medical encounter data prior to
cohort entry date, ≥1 medical encounter resulting in a clinical
note within the prior year, ≥1 outpatient encounter in the previ-
ous year, ≥1 diagnosis or affirmed mention of ED within the
previous year (ICD-9-CM codes 607.84 or 302.72 and corre-
sponding ICD-10 codes), no prescriptions for other PDE5
inhibitor, nitrates, riociquat, or alpha-blockers in the previous
year, and no outcome of interest or pulmonary arterial hyperten-
sion in the previous year.
Because PDE5 inhibitor medications do not have a common
use pattern across patients, the duration of possession is not
determined solely by indicators such as quantity dispensed or
days supplied. Thus, possession periods were then defined to cor-
respond to the time patients likely had possession of the medica-
tion. For each prescription event, the duration of possession was
defined as the median time between consecutive prescriptions,
with strata of days supplied and number of refills, plus an addi-
tional 5 days. In the absence of a new prescription, possession
was defined as uncertain up to the 90th percentile of the inter-
prescription interval. Outcomes and person-time in this uncer-
tain period are not included in this study in order to mitigate any
potential bias to the null due to incorrect attribution of events.
Following the uncertain period patients were assumed to be in
the non-possession period. If multiple prescriptions for tadalafil
or anti-hypertensive medication were observed on the same day,
the days of possession were set to the longest estimated posses-
sion period. Anti-hypertensive medications were presumed to be
taken chronically and daily or routinely during the span of time
that patients had an active prescription. During periods of co-
possession, we do not know the timing or frequency of co-expo-
sure; however, we infer that co-possession periods represent the
span of time during which co-exposure is most likely.
The tadalafil + anti-hypertensive cohort is defined as the peri-
ods of time where there was concomitant possession (co-posses-
sion) of both medications, the tadalafil-only cohort is defined as
the period of time with only possession of tadalafil, and the anti-
hypertensive-only cohort is defined as the period of time with
only anti-hypertensive medication. Individual possession periods
were identified; the same patient could contribute to multiple
Nunes et al
possession periods if all the inclusion criteria were met for each
one.
Outcomes
The primary objective of this study was to quantify and com-
pare the rate of select hypotensive or cardiovascular outcomes in
patients with ED, during medication possession periods of
tadalafil + anti-hypertensive medication co-possession, relative to
matched periods of anti-hypertensive possession only. The sec-
ondary objective was to quantify and compare these outcomes in
patients with tadalafil + anti-hypertensive medication co-posses-
sion, relative to tadalafil only possession.
Cardiovascular outcomes were identified from the day follow-
ing the start of a medication possession period until; exit from
data capture, end of the possession period, or study end date.
Cardiovascular outcomes were identified by diagnostic codes and
NLP algorithms. Outcomes identified by diagnostic codes were;
hypotension, syncope, myocardial infarction, unstable angina or
angina/chest pain, stroke and transient ischemic attack (TIA),
ventricular arrhythmia/cardiac arrest, hospitalization for heart
failure, and death (Supplementary Materials, Table S1). Cardio-
vascular death was defined as death with a diagnosis of myocar-
dial infarction, stoke, sudden cardiac death occurring on the date
of death or preceding 30 days. Outcomes that were identified by
NLP of the free-text notes include dizziness, fainting, hypoten-
sion, pre-syncope and syncope. The NLP was used to identify
mentions of specified outcomes (Supplementary Materials,
Table S2) and the note section was characterized as supporting,
neutral or detracting, and sentiments and attributes were charac-
terized as affirming, suggestive, or negating; mentions were char-
acterized as an outcome if the note section was supportive and
the sentiment was affirming or suggestive or if the note section
was neutral and the sentiment was affirming. Outcomes were
attributed to the exposure cohort at the time the outcome
occurred.
Covariates
A baseline period of 12 months prior to medication posses-
sion was defined for each possession period. Covariates include;
demographics (age, race/ethnicity, geographic region, calendar
time), medical utilization (insurance status, medical encounters,
length of stay, provider specialty), behavioral characteristics (alco-
hol use, tobacco use), comorbidities and medications. Specified
comorbidities included hypotensive events, hypertension,
peripheral vascular disease, angina, heart failure, myocardial
infarction, stroke, arrhythmia, congestive heart failure, prostatec-
tomy, prostate cancer, depression, dyslipidemia, obesity, diabe-
tes, and the Charlson Comorbidity Index.20
Statistical Analysis
Statistical analysis was performed on SAS v9.4 software. Pro-
pensity score models were used to address the imbalance between
J Sex Med 2022;19:74−82
Tadalafil With Antihypertensive Medications
the cohorts. Propensity scores were estimated by unconditional
logistic regression analyses incorporating the pre-specified covari-
ates and empirically-identified covariates based on the top 100
most frequently occurring diagnoses, procedures and medications
identifies in the baseline period. To accommodate changes in pre-
scribing patterns the propensity score model was estimated within
separate strata of calendar time (January 1, 2012−December 31,
2013, January 1, 2014−September 30, 2015, October 1, 2015
−December 30, 2017). The final cohorts were selected by a 1:1
match, one matched comparator possession period was sought for
each tadalafil + anti-hypertensive possession period relying on
greedy matching where the closest available match is identified.21
Patients may contribute to multiple and different possession peri-
ods, and therefore self-matching was possible.
Patient characteristics pre- and post-propensity score match were
assessed descriptively, with frequencies and percentages for categori-
cal variables and mean, standard deviations (SD) and median, inter-
quartile ranges (IQRs) provided for continuous variables.
For each cardiovascular outcome, incidence rates, reported as
the number of events in the cohort per 1,000 person-years were
calculated for the possession periods in the matched cohorts. A
matched-adjusted Poisson model including age, days since first
ED diagnosis, possession period sequence, and indicators for
uninsured, number of inpatient stays, and number of emergency
room visits was used to determine the adjusted-matched IR and
incident rate ratios (IRRs), which were calculated as the IR for
tadalafil + anti-hypertensive/IR for anti-hypertensive or tadalafil
only, with 95% confidence intervals (CIs).
Sensitivity Analysis
Sensitivity analyses were conducted on the propensity score-
matched possession periods estimating IRs and IRRs for subgroups
of anti-hypertensive categories; anti-hypertensive classes (calcium
channel blockers, beta blockers, renin-angiotensin system inhibitors,
diuretics, and other) or the number of anti-hypertensive medica-
tions at the start of the possession period (1 or ≥2).
Qualitative Analyses
Qualitative summaries were generated from a manual review of
patients virtual (v)EHRs which provide a chronological listing of rel-
evant EHR information. The NLP system was used to extract and
organize concepts from the free-text fields into semi-structured
fields. To ascertain whether and how clinicians considered anti-
hypertensive medication status when prescribing tadalafil, prescrib-
er’s rationale was inferred by clinician review of 250 vEHRs of
patients identified with co-possession of tadalafil and anti-hyperten-
sive, and 100 vEHRs of patients with ED and anti-hypertensive
medication not prescribed tadalafil. The vEHRs were categorized
according to CVD status (chronic-symptomatic, chronic-asymp-
tomatic, acute-recent, and acute past) and anti-hypertensive medica-
tion status (initiation, prevalent, discontinuation). Within these
categories, the reviewing clinician identified whether there was any
J Sex Med 2022;19:74−82
77
documentation that tadalafil or other PDE5 inhibitors were dis-
cussed. If discussed, the reviewing clinician documented the nature
of the discussion. From among the vEHRs, 200 source free text
notes were requested for manual review.
RESULTS
Patient Characteristics
Of the approximate 4 million male patients with either a
PDE5 inhibitor or anti-hypertensive prescription in the EHR
database, 634,119 had at least one diagnosis or affirmed mention
of ED. Following application of inclusion criteria 360,154
patients had at least 1 eligible possession period; 54,299 patients
had a tadalafil + anti-hypertensive possession period, 295,619
patients had an anti-hypertensive only possession period, 55,861
had a tadalafil only possession period (Figure 1). In total there
were 127,849 tadalafil + anti-hypertensive medication possession
periods, 821,359 anti-hypertensive only medication possession
periods, and 98,638 tadalafil only medication possession periods
over the study period (Table 1).
When matching to anti-HTN possession periods, 99% of
tadalafil + anti-hypertensive possession periods were successfully
matched resulting in 126,120 matched possession periods for
each treatment; 2 (<0.01%) of these were self-matched. How-
ever, only 20% of tadalafil + anti-hypertensive were successfully
matched to tadalafil only possession periods, resulting in 26,416
matched possession periods for each treatment. The low match-
ing success was driven by the strong association between baseline
hypertension and anti-hypertensive medication and a relatively
small pool of potential matches. Due to the potential for residual
confounding for differences in unobserved covariates, the analysis
comparing tadalafil + anti-hypertensive to tadalafil only was
deprioritized and is not presented in the main text (Supplemen-
tary Materials, Figure S1, Table S3).
Before propensity score matching, the patients in
tadalafil + anti-hypertensive periods were younger, more likely to
be commercially insured and had fewer baseline comorbidities
compared to patients in the anti-HTN only periods (Table S4).
Differences of greater than 5% in the distribution of pre-
matched covariates were considered indicative of a notable imbal-
ance. Of those with tadalafil possession periods, 53% had an
observed period with co-possession of anti-hypertensive medica-
tion; the median (IQR) overlap of periods was 191 (108−351)
days. After propensity score matching, the largest proportion of
patients were in the 55−64 years age group, the majority were
white, had commercial health insurance, around half were cur-
rent or past smokers, and most had hypertension and/or hyper-
lipidemia/dyslipidemia at baseline (Table 2).
Incidence Rate Ratios
The adjusted-matched IRRs for the anti-hypertensive only
possession periods compared to tadalafil + anti-hypertensive
78 Nunes et al

Figure 1. Flow diagram of patient and possession period eligibility.

*Counts are the number of unique patients within each cohort. Patients may be represented in more than one cohort, thus the sum of
the cohort-specific counts exceeds 360,154. ED, erectile dysfunction; PDE, phosphodiesterase.

periods of diagnosed outcomes were all below 1, however only
ventricular arrhythmia (IRR 0.79; 95% CI 0.66, 0.94) and diag-
nosis of hypotension (IRR 0.79; 95% CI 0.71, 0.89) had 95%
CI below 1 (Figure 2). This was also seen for death from any
cause (IRR 0.55; 95% CI 0.36, 0.86), but not for CV-related
death (IRR 0.66; 95% CI 0.26, 1.66) (Figure 2). The adjusted-
matched IRRs for NLP-identified outcomes were also below 1,
only the IRR for dizziness and fainting was statistically significant
(IRR 0.88, 95% CI 0.81, 0.95) (Figure 2). All IRR values for CV
events and CV-related death were lower in the tadalafil + anti-
hypertensive possession periods versus the anti-hypertensive peri-
ods only.
Qualitative Analyses
Of the sample vEHR of 250 patients with tadalafil and anti-
hypertensive co-possession, only 3 (1%) contained
documentation that the healthcare providers had discussions
with their patients pertaining to the risks associated with joint
exposure to tadalafil and anti-hypertensive medications. Of the
sample of 100 vEHR of patients with anti-hypertensive medica-
tion only, none had evidence of discussions of tadalafil and anti-
hypertensive risks.
Sensitivity Analyses
IRRs were similar across strata of anti-hypertensive classes and
number of anti-hypertensive medications at cohort entry, and
were consistent with the primary analysis in that all associations
were either null or significantly less than 1 (Table S5). For the
comparison of Cialis + Anti-HTN to Anti-HTN only, results
were comparable within strata of matched patients with only one
anti-HTN prescribed and those with 2 or more co-prescribed
classes of anti-HTN medications.

Table 1. Possession period characteristics among patient cohort

Possession period Patients (n) DISCUSSION
≥1 eligible possession period 360,154 Previous clinical studies have indicated that concomitant use
≥1 tadalafil + anti-hypertensive 54,299 of a PDE5 inhibitor with anti-hypertensive medication may lead
≥1 anti-hypertensive only 295,619 to drops in blood pressure.16 However, it is unclear whether co-
≥1 tadalafil only 55,861 possession of a PDE5 inhibitor in a prescription environment
All tadalafil + anti-hypertensive 127,849 with anti-hypertensive medication results in significant risks or
All anti-hypertensive only 821,359 clinically identifiable hypotensive or cardiovascular outcomes in
All tadalafil only 98,638 the real world. The results from this study begin to address this
≥, more than or equal to. question and suggest that patients with physician-enabled co-

J Sex Med 2022;19:74−82

Tadalafil With Antihypertensive Medications 79

Table 2. Characteristics of participants with tadalafil + anti-hypertensive and anti-hypertensive possession periods after propensity score
matching
Tadalafil + anti-hypertensive (N = 126,120) Anti-hypertensive only (N = 126,120)
Age, years, n (%)
18−34 605 (0.5) 562 (0.5)
35−44 6,315 (5.0) 6,300 (5.0)
45−54 28,015 (22.2) 28,154 (22.3)
55−64 51,735 (41.0) 52,087 (41.3)
65−74 31,466 (25.0) 31,355 (24.9)
≥75 7,984 (6.3) 7,662 (6.1)
Race, n (%)
White 99,578 (79.0) 99,418 (78.8)
Black/African American 18,944 (15.0) 19,048 (15.1)
Hispanic 3,051 (2.4) 3,071 (2.4)
Asian 983 (0.8) 993 (0.8)
Other 3,564 (2.8) 3,590 (2.9)
Type of health insurance, n (%)
Commercial 77,237 (61.2) 76,417 (60.6)
Public (Medicare or Medicaid) 21,852 (17.3) 21,276 (16.9)
Commercial and public 11,680 (9.3) 12,333 (9.8)
Uninsured 2,014 (1.6) 1,720 (1.4)
Unknown 13,337 (10.6) 14,374 (11.4)
Smoker, n (%)
Current 18,311 (14.5) 18,271 (14.5)
Past 47,066 (37.3) 47,105 (37.4)
Never 51,417 (40.8) 51,527 (40.9)
Other/unknown 9,326 (7.4) 9,217 (7.3)
Comorbidities
Hypotension 1,506 (1.2) 1,463 (1.2)
Hypertension 112,232 (89.0) 112,228 (89.0)
Peripheral vascular disease 3,815 (3.0) 3,650 (2.9)
Angina 249 (0.2) 241 (0.2)
Heart failure 3,413 (2.7) 3,407 (2.7)
Myocardial infarction 1,269 (1.0) 1,286 (1.0)
Stroke 2,592 (2.1) 2,568 (2.0)
Arrhythmia 544 (0.4) 522 (0.4)
Hyperlipidemia 88,242 (70.0) 88,083 (69.8)
Prostatectomy 652 (0.5) 630 (0.5)
Prostate cancer 5,706 (4.5) 5,683 (4.5)
Depression 12,711 (10.1) 12,871 (10.2)
Dyslipidemia 88,434 (70.1) 88,331 (70.0)
Obesity 75,772 (60.1) 75,837 (60.1)
Diabetes 37,645 (29.9) 37,975 (30.1)
Charlson comorbidity index
0−1 93,511 (74.1) 93,642 (74.3)
2−3 23,896 (19.0) 23,881 (18.9)
4−5 5,806 (4.6) 5,754 (4.6)
6−7 1,904 (1.5) 1,851 (1.5)
≥8 1,003 (0.8) 992 (0.8)

possession of tadalafil and anti-hypertensive medications may not
have an increased risk of hypotensive or cardiovascular outcomes
in the real world beyond that observed among patients in posses-
sion of anti-hypertensive medications only. Hypertension
remains the leading cause of death globally,2 highlighting the
importance of blood pressure control. In the US, thiazide diu-
retics, calcium channel blockers, ACE inhibitors or ARBs are
recommended as first line therapy for stage 1 hypertension, 2
first-line drugs of different classes are recommended for stage 2
hypertension and a diuretic should be a component of treatment
for resistant hypertension.14 ED may be an adverse effect of thia-
zide diuretics, and beta-blockers,4 but for physicians, simply
removing a medication from treatment for hypertension is often
not an option as optimal treatment for the control of

J Sex Med 2022;19:74−82

80
Figure 2. Adjusted-matched incidence rate ratios for tadalafil + anti-hypertensive relative to anti-hypertensive only possession periods
*IR shown as rate per 1,000 person-years
Natural language processing extracts data from structured data elements and free text clinical notes within electronic health records. CI,
confidence interval; CV, cardiovascular; IRR, incidence rate ratio.
hypertension can be difficult to achieve. Despite this, patients
faced with ED often discontinue their anti-hypertensive medica-
tion, without consultation of a physician; as observed in a long-
term study of antihypertensive medication, sexually related side
effects caused discontinuation of treatment in 8.3% of male
participants.22
The Princeton Consensus (Expert Panel) Conference is a
multispecialty collaborative tradition dedicated to optimizing
sexual function and preserving cardiovascular health. Since 2010,
recommendations have included that patients whose blood pres-
sure is well controlled with more than one antihypertensive med-
ication may safely receive approved medical therapies for sexual
dysfunction under a physician’s care.23,24 Awareness by physi-
cians of the options available to treat ED side effects of antihy-
pertension medications are therefore key for aiding patient
adherence and optimal regulation of blood pressure.13 In addi-
tion, physician and patient awareness of safety aspects associated
with co-possession of such medicines through real-world studies,
such as the one reported here, is of paramount importance.
Strengths and limitations of this study include that EHR data
are valuable for examination of clinical health care outcomes and
treatment patterns in the real world. However, EHR data is also
associated with inherent limitations as the data are retrospective
and collected for the purpose of clinical patient management,
not for research. EHR data capture the proportion of medical
interactions occurring only at facilities contributing to Optum’s
EHR database. We have further limited the population to the
subset of those with evidence of routine utilization in order to
Nunes et al
minimize the potential for missed prescriptions or diagnoses. In
addition, prescription data represent the intent of the prescriber
and do not indicate that a medication was taken as prescribed
and as tadalafil use patterns can vary greatly between patients,
the time of exposure is uncertain. For this reason, exposures were
referred to as co-possession periods as opposed to periods of co-
use. Also, co-medication, diagnosis and procedures received out-
side of the provider network captured in the EHR may not have
been recorded. Study outcomes were identified via a combina-
tion of structured diagnostic codes and NLP of the free text clini-
cal notes; use of NLP enables the identification of less serious
outcomes, such as dizziness, that may not receive a diagnostic
code. The free text notes were manually adjudicated and it was
observed that the NLP accurately captured explicit negations and
affirmations. Patients included were co-medicated for several
months before the beginning of the study period, so those with
outcomes from the start of the study may not be well represented
here. The design and methodology was intended to assess inci-
dence rate ratios after adjusting for underlying disease; however,
differences in baseline covariates suggest that there is a potential
for residual confounding and channeling bias, for example,
healthier ED and HTN patients could be more likely to receive a
tadalafil prescription along with antihypertensive medication
after careful review by a physician and less healthy patients could
be more likely to receive a prescription for anti-hypertensive
medication/s only while restricting access of the PDE5 medica-
tions. This form of bias should be attenuated due to the propen-
sity score matching, but because of unobserved patient
characteristics (eg, sexual activity and social correlates of sexual
J Sex Med 2022;19:74−82
Tadalafil With Antihypertensive Medications
activity) and gradients in severity of the matched factors that are
not fully reflected in the EHR data (eg, severity of hypertension,
missing blood pressure and severity of comorbidity data), resid-
ual bias cannot be ruled out. Lastly, we acknowledge that the
interaction between alpha blockers and PDE5 inhibitors may be
of significance and helpful in selected patients with resistant
hypertension.25 However, this was considered out of scope for
the current study as we examined the drug-drug interactions
between the major classes of anti-hypertensive medications, and
alpha blockers are relegated to fourth or fifth line treatment for
hypertension due to the risk of hypotensive and cardiac events.26
−28
However, this question is scientifically relevant and could be
addressed in future studies.
This is the first study to our knowledge using innovative NLP
to evaluate co-possession and hypotensive/cardiovascular out-
comes in among patients with tadalafil and anti-hypertensive
medication possession. These real world patients with co-posses-
sion of tadalafil and anti-hypertensive medication were identified
within a large EHR database. One of the benefits of this study is
it is able to utilize large databases sourced from EHRs with free-
text notes of discussions between the doctor and patient. These
discussions are processed in a manner that is machine-readable
and therefore searchable, providing an additional source of data
to research adverse events. This study did not demonstrate an
increased risk of hypotensive/CV outcomes in patients with co-
possession of tadalafil and anti-hypertensive medications beyond
that observed among patients in possession of anti-hypertensive
medications only.
Corresponding Author: Thomas McGraw, PhD, Sanofi, 55
Corporate Drive, Bridgewater, NJ 08807, USA, Tel: +1 908
981-3067; E-mail: Thomas.McGraw@sanofi.com
Conflict of Interest: AN and JS are employees of Optum, which
was under contract to Sanofi to conduct this work.
AS, AG and TM are employees of Sanofi and may hold shared
and/or stock options in the company.
Funding: This study was funded by Sanofi. Employees of Sanofi
contributed to all aspects of the study.
STATEMENT OF AUTHORSHIP
Anthony P. Nunes: Conceptualization, Methodology, Valida-
tion, Formal Analysis, Investigation, Resources, Data Curation,
Writing − original draft, Writing − review and editing, Visuali-
zation, Software; John D. Seeger: Conceptualization, Methodol-
ogy, Validation, Formal Analysis, Investigation, Resources, Data
Curation, Writing − original draft, Writing − review and edit-
ing, Visualization, Software; Andrew Stewart: Conceptualization,
Methodology, Validation, Formal Analysis, Investigation,
Resources, Data Curation, Writing − original draft, Writing −
review and editing, Visualization, Project Administration, Fund-
ing Acquisition; Alankar Gupta: Conceptualization,
J Sex Med 2022;19:74−82
81
Methodology, Formal Analysis, Investigation, Resources, Data
Curation, Writing − original draft, Writing − review and edit-
ing, Supervision, Project Administration, Funding Acquisition;
Thomas McGraw: Conceptualization, Methodology, Formal
Analysis, Investigation, Resources, Data Curation, Writing −
original draft, Writing − review and editing, Supervision, Project
Administration.
REFERENCES
1. Selvin E, Burnett AL, Platz EA. Prevalence and risk factors for
erectile dysfunction in the US. Am J Med 2007;120:151–157.
doi: 10.1016/j.amjmed.2006.06.010.
2. GBD 2017 Risk Factor Collaborators. Global, regional, and
national comparative risk assessment of 84 behavioural, envi-
ronmental and occupational, and metabolic risks or clusters of
risks for 195 countries and territories, 1990-2017: A systematic
analysis for the Global Burden of Disease Study 2017. London,
England: Lancet 2018;392:1923–1994. doi: 10.1016/s0140-
6736(18)32225-6.
3. Centers for Disease Control and Prevention (CDC). Estimated
hypertension prevalence, treatment, and control among U.S.
adults. 2019. Available at: https://millionhearts.hhs.gov/data-
reports/hypertension-prevalence.html. Accessed December 11,
2020.
4. Mobley DF, Khera M, Baum N. Recent advances in the treat-
ment of erectile dysfunction. Postgrad Med J 2017;93:679–
685. doi: 10.1136/postgradmedj-2016-134073.
5. Feldman DI, Cainzos-Achirica M, Billups KL, et al. Subclinical
vascular disease and subsequent erectile dysfunction: The
Multiethnic Study of Atherosclerosis (MESA). Clin Cardiol
2016;39:291–298. doi: 10.1002/clc.22530.
6. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence
and its medical and psychosocial correlates: Results of the
Massachusetts Male Aging Study. J Urol 1994;151:54–61.
doi: 10.1016/s0022-5347(17)34871-1.
7. Miner M, Parish SJ, Billups KL, et al. Erectile dysfunction and
subclinical cardiovascular disease. Sex Med Rev 2019;7:455–
463. doi: 10.1016/j.sxmr.2018.01.001.
8. Montorsi F, Briganti A, Salonia A, et al. Erectile dysfunc-
tion prevalence, time of onset and association with risk
factors in 300 consecutive patients with acute chest pain
and angiographically documented coronary artery disease.
Eur Urol 2003;44:360–364. doi: 10.1016/s0302-2838
(03)00305-1.
9. Uddin SMI, Mirbolouk M, Dardari Z, et al. Erectile dysfunction
as an independent predictor of future cardiovascular events:
The multi-ethnic study of atherosclerosis. Circulation
2018;138:540–542. doi: 10.1161/circulationaha.118.033990.
10. Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dys-
function and subsequent cardiovascular disease. JAMA
2005;294:2996–3002. doi: 10.1001/jama.294.23.2996.
11. Seftel AD, Sun P, Swindle R. The prevalence of hypertension,
hyperlipidemia, diabetes mellitus and depression in men with
erectile dysfunction. J Urol 2004;171:2341–2345. doi:
10.1097/01.ju.0000125198.32936.38.
82
12. Sun P, Swindle R. Are men with erectile dysfunction more likely
to have hypertension than men without erectile dysfunction? A
naturalistic national cohort study. J Urol 2005;174:244–248.
doi: 10.1097/01.ju.0000162050.84946.86.
13. Viigimaa M, Vlachopoulos C, Doumas M, et al. Update of the
position paper on arterial hypertension and erectile dysfunction.
J Hypertens 2020;38:1220–1234. doi: 10.1097/hjh.000000
0000002382.
14. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/
AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guide-
line for the prevention, detection, evaluation, and management
of high blood pressure in adults: Executive summary: A report
of the American College of Cardiology/American Heart Associa-
tion Task Force on Clinical Practice Guidelines. J Am Coll Car-
diol 2018;71:2199–2269. doi: 10.1016/j.jacc.2017.11.005.
15. Al Khaja KAJ, Sequeira RP, Alkhaja AK, et al. Antihypertensive
drugs and male sexual dysfunction: A review of adult hyper-
tension guideline recommendations. J Cardiovasc Pharmacol
Ther 2016;21:233–244. doi: 10.1177/1074248415598321.
16. Kloner RA. Cardiovascular effects of the 3 phosphodiesterase-
5 inhibitors approved for the treatment of erectile dysfunction.
Ci rc ulation 2 00 4; 110 :3 14 9 – 3 1 5 5 . do i : 1 0 . 1 16 1 / 0 1.
CIR.0000146906.42375.D3.
17. Kloner RA, Goldstein I, Kirby MG, et al. Cardiovascular safety
of phosphodiesterase type 5 inhibitors after nearly 2 decades
on the market. Sex Med Rev 2018;6:583–594. doi: 10.1016/
j.sxmr.2018.03.008.
18. Nunes AP, Loughlin AM, Qiao Q, et al. Tolerability and effec-
tiveness of exenatide once weekly relative to basal insulin
among type 2 diabetes patients of different races in routine
care. Diabetes Ther 2017;8:1349–1364. doi: 10.1007/
s13300-017-0314-z.
19. Nunes AP, Yang J, Radican L, et al. Assessing occurrence of
hypoglycemia and its severity from electronic health records
of patients with type 2 diabetes mellitus. Diabetes Res Clin
Pract 2016;121:192–203. doi: 10.1016/j.diabres.2016.09.
012.
20. Charlson M, Szatrowski TP, Peterson J, et al. Validation of a
combined comorbidity index. J Clin Epidemiol 1994;47:1245–
1251. doi: 10.1016/0895-4356(94)90129-5.
21. Parsons L. Reducing bias in a propensity score matched-pair
sample using greedy matching techniques. The Twenty-Sixth
Nunes et al
Annual SAS Users Group International Conference; 2001. p.
214–226.
22. Curb JD, Borhani NO, Blaszkowski TP, et al. Long-term sur-
veillance for adverse effects of antihypertensive drugs. JAMA
1985;253:3263–3268.
23. Nehra A, Jackson G, Miner M, et al. The Princeton III Consen-
sus recommendations for the management of erectile dys-
function and cardiovascular disease. Mayo Clin Proc
2012;87:766–778. doi: 10.1016/j.mayocp.2012.06.015.
24. Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and
cardiac risk (the Second Princeton Consensus Conference).
Am J Cardiol 2005;96:313–321. doi: 10.1016/j.amj-
card.2005.03.065.
25. Hundemer GL, Knoll GA, Petrcich W, et al. Kidney, cardiac,
and safety outcomes associated with a-blockers in patients
with CKD: A population-based cohort study. Am J Kidney Dis
2021;77:178–189.e171. doi: 10.1053/j.ajkd.2020.07.018.
26. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guide-
lines for the management of arterial hypertension: the Task
Force for the management of arterial hypertension of the
European Society of Hypertension (ESH) and of the European
Society of Cardiology (ESC). J Hypertens 2013;31:1281–1357.
doi: 10.1097/01.hjh.0000431740.32696.cc.
27. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/
AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA
guideline for the prevention, detection, evaluation, and man-
agement of high blood pressure in adults: Executive summary:
A report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guidelines.
H y p e r te n s i o n 2 0 1 8 ; 7 1 : 1 2 6 9– 1324. doi: 1 0 . 1 1 6 1 /
hyp.0000000000000066.
28. Leung AA, et al. Hypertension Canada's 2017 guidelines for
diagnosis, risk assessment, prevention, and treatment of
hypertension in adults. Can J Cardiol 2017;33:557–576. doi:
10.1016/j.cjca.2017.03.005.
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article can be
found in the online version at https://doi.org/10.1016/j.
jsxm.2021.10.012.
J Sex Med 2022;19:74−82