HELPDESK ANSWERS
substance use disorder.3 It also recommended against
medically supervised withdrawal because it was associ-
ated with higher rates of relapse, leading to worse out-
comes. The committee did not endorse the use of
buprenorphine or methadone over the other.
Carrie Anderson, MD
Amity Onders, MD
Franciscan Health Indianapolis FMR
Indianapolis, IN
The authors declare no conflicts of interest.
References
1. Zedler B, Mann A, Kim M, et al. Buprenorphine compared
with methadone to treat pregnant women with opioid use
disorder: a systematic review and meta-analysis of safety in
the mother, fetus and child. Addiction. 2016; 111:
2115–2128. [STEP 1]
2. Jones H, Kaltenbach K, Heil S, et al. Neonatal abstinence
syndrome after methadone or buprenorphine exposure.
N Engl J Med. 2010; 363:2320–2331. [STEP 2]
3. ACOG Committee Opinion Number 711. Opioid use and
opioid use disorder in pregnancy. Obstet Gynecol. 2017;
130(2):e81–e94. [STEP 3]
Is pindolol plus an SSRI superior to an
SSRI alone in treating patients with
panic disorder?
EVIDENCE-BASED ANSWER
Possibly. Augmentation of SSRIs with the beta-
blocker pindolol improves various symptom scores
and is associated with decreased frequency of panic
attacks and diminished panic symptoms in patients
with treatment-refractory panic disorder (SOR: C,
systematic review with single small randomized
controlled trial and small case series).
Copyright © 2019 by Family Physicians Inquiries Network, Inc.
DOI 10.1097/EBP.0000000000000167
A 2016 systemic review of 11 randomized controlled
trials (RCTs) and observational studies that eval-
uated augmentation therapies for treatment-resistant
panic disorder included only one small RCT in-
vestigating the use of pindolol with SSRIs.1 This 2000
32 Volume 22 • Number 2 • February 2019
Copyright © 2019 by Family Physicians Inquiries Network, Inc. Unauthorized reproduction of this article is prohibited.
RCT (N550) examined pindolol augmentation in oth-
erwise well patients with SSRI-resistant panic disorder
with or without agoraphobia diagnosed by Diagnostic
and Statistical Manual of Mental Disorders-IV criteria.2
Participants were between 18 and 72 years old
and had previously been treated with at least two
antidepressants. Patients with additional axis one di-
agnoses, major medical conditions, or contra-
indications to beta-blockers were excluded. All
participants received 20 mg fluoxetine daily for 8
weeks. After this time period, patients who self-
reported ,20 percent improvement in anxiety and
panic symptoms (N526) were admitted to the double-
blind placebo trial. Participants were randomized to
receive 2.5 mg pindolol three times daily (N513) or an
identical placebo (N513); all patients continued taking
fluoxetine 20 mg/daily. After 4 weeks, the patients
were assessed weekly in the clinic and completed six
clinical questionnaires (Hamilton Rating Scale for
Anxiety [HAM-A]; Hamilton Rating Scale for De-
pression [HAM-D]; Panic Self Questionnaire [PSQ];
National Institute of Mental Health Anxiety Scale;
Clinical Anxiety Scale Plus Panic Attacks [CAS+PA];
and Clinical Global Impression [CGI] scale) at each
visit. Of the 26 patients, 25 (52% women) completed
the study. Adjusting for age differences noted between
the groups, pindolol plus fluoxetine led to significant
improvement on all clinical measures except the HAM-
D over the 4 weeks. By week 2, the pindolol plus flu-
oxetine group had better scores than fluoxetine alone
on the HAM-A (7.1 vs 10 points on a 0 to 56 scale,
P,.02), the PSQ (3.2 vs 4.7 panic attacks per week,
P,.01), the CAS+PA (11 vs 16 points on a 0 to 100
scale, P,.01), and the CGI (2.5 vs 3.8 points on a 0 to 4
scale, P,.02). How the observed differences in scales
translated to meaningful, durable, patient-oriented
outcomes was not discussed. No serious side effects
were reported.
A 2000 abstract of an extremely small case series
of inpatients (N53) with panic disorder diagnosed by
DSM-IV criteria reported the effect of pindolol augmenta-
tion of SSRI therapy on panic symptoms.3 It was not clear
whether patients had treatment-refractory panic disor-
der. Patients received pindolol 2.5 mg three times daily
and either paroxetine or citalopram 10 mg/d for an un-
disclosed period. All three patients reported improve-
ment in panic disorder symptoms and no increase in
panic attacks; clinical outcome measures and statistical
results were not provided.
Evidence-Based Practice
 HELPDESK ANSWERS
Abigail Shea
Colby College, Waterville, ME
W. Gregory Feero, MD, PhD
Maine Dartmouth Family Medicine Residency
Augusta, ME
The authors declare no conflicts of interest.
References
1. Freire RC, Zugliani MM, Garcia RF, Nardi AE. Treatment-
resistant panic disorder: a systematic review. Expert Opin
Pharmacother. 2016; 17(2):159–168. [STEP 1]
2. Hirschmann S, Dannon PN, Iancu I, et al. Pindolol aug-
mentation in patients with treatment-resistant panic disor-
der: a double-blind, placebo-controlled trial. J Clin
Psychopharmacol. 2000; 20(5):556–559. [STEP 2]
3. Ziegenbein M, Steiger A, Murck H. 266. Treatment with the
presynaptic 5-HT1A-antagonist pindolol in patients with panic
disorder. Biol Psychiatry. 2000; 47(8)(suppl 1):S81. [STEP 4]
Does distance running lead to increased
risk of severe cardiovascular events?
EVIDENCE-BASED ANSWER
The absolute risk of having a severe cardiovascular
event while running a half marathon or marathon is
approximately 0.14 to 0.63 events/100,000 mara-
thon hours compared with a general 0.0083 cardiac
arrest events/100,000 hours in adult patients (SOR:
B, cohort studies).
Copyright © 2019 by Family Physicians Inquiries Network, Inc.
DOI 10.1097/EBP.0000000000000168
I n 2016, a 6-year multirace prospective cohort study
(N5511,880) examined the rate of life-threatening
cardiovascular events during marathons and half
marathons in Paris.1 Participants were men and
women more than 18 years old who registered for the
marathon and half marathon in the Registre des Acci-
dents Cardiaques lors des courses d’Endurance Paris
Registry. Eighty percent were male and the mean age
of participants was ,40 years old. All runners who
started the race were observed and monitored for ad-
verse outcomes 30 minutes before to 2 hours after the
Evidence-Based Practice
Copyright © 2019 by Family Physicians Inquiries Network, Inc. Unauthorized reproduction of this article is prohibited.
race, regardless of race completion. The primary out-
come was a composite rate of death and life-
threatening cardiovascular events requiring medical
intervention and hospital admission for at least 24
hours. A total of 13 life-threatening cardiovascular
events occurred, including nine cardiac arrests. Of
these cardiac arrests, seven were successfully re-
suscitated and three died. Of the cardiovascular
events, 9 of the 13 occurred at or within 2 miles of the
finish line. The other four occurred within the first 4
miles of the races. The major cardiovascular event rate
(2.5/100,000; 95% CI, 1.2–3.9) was no different be-
tween the marathon (2.0/100,000; 95% CI, 0–4.2) and
the half-marathon distances (2.8/100,000; 95% CI,
1.1–4.5), P5.81. This cohort study was limited by self-
selection into the race and a lower-than-average
number of female participants.
A 2012 cohort study of 59 different marathons and
half marathons (N511 million registered participants
over 10 years) examined the rate of cardiac arrests in
runners during marathons and half marathons.2 Partic-
ipants were 48% to 51% male. The primary outcome
was cardiac arrest that occurred during or within 1 hour
of completion of the race. A total of 59 cardiac arrests
were identified among registered race participants with
the majority of these (40 of 59) during the marathon.
Compiled rate of cardiac arrest was 0.54/100,000 run-
ners (95% CI, 0.41–0.70). Rate of cardiac arrest was
higher during the marathon (1.01/100,000; 95% CI,
0.72–1.4) than during the half marathons (0.27/
100,000; 95% CI, 0.17–0.43; P,.001). Of the 59 run-
ners who experienced cardiac arrest, 42 died. For those
with available clinical data, hypertrophic cardiomyopa-
thy, either confirmed or suspected, was the most com-
mon cause of cardiac arrest (15 of 23). One limitation of
this study was that it was based on the number of reg-
istered participants, not the number of individuals who
started the race, which could lead to overestimation of
event rates.
In 2018, the American Heart Association reported on
heart disease and stroke statistics.3 For outside-of-hospital
suspected cardiac arrest, emergency medical services
(EMS) assessed 141/100,000 population (95% CI,
138–143). EMS treated 57/100,000 any age population
(95% CI, 56–59) and 73/100,000 (95% CI, 71–75) popu-
lation of adults only. When adjusted for age and sex, the
annual incidence of EMS treated suspected cardiac arrest
was 60/100,000 (95% CI, 54–66) population.
Volume 22 • Number 2 • February 2019 33