[DYSPHAGIA] ACE and cough

[eripley@yahoo.com (Irene Campbell-Taylor)]

I have had a number or requests re ACEs and chronic
cough.
Please see the following:

Bronchospasm and cough as adverse reactions to the ACE
inhibitors captopril, enalapril and lisinopril.       
                       A controlled retrospective
cohort study.   Br J Clin Pharmacol 1995
Mar;39(3):265-70    Wood R
 1. We report a controlled retrospective cohort study
of respiratory adverse reactions to ACE inhibitors.
Bronchospasm and
cough occurred at a higher rate in patients treated
with ACE inhibitors, no links with sex, past history
of bronchospasm, drug
type or dose were found. 2. Cohorts of 1013 patients
on angiotensin converting enzyme (ACE) inhibitors and
1017
patients on lipid lowering drugs (LLDs) were compared
for the occurrence of new bronchospasm, relapse of
previous
bronchospasm, increase of current bronchospasm, and
cough. 3. The prevalence of bronchospasm was 5.5% for
patients on
ACE inhibitors and 2.3% for patients on LLDs, P <
0.001. The relative risk of a bronchospasm adverse
reaction for a patient
on an ACE inhibitor compared with a patient on a LLD
was 2.39, 95% confidence interval 1.47 to 3.90. 4. No
ACE
inhibitor specificity, or significant sex differences
were found in the prevalence of bronchospasm or cough
after correcting for
bias implicit in the original cohorts. The
bronchospastic reactions were not dose dependent. 5.
The prevalence of a past history
of bronchospasm in patients reporting ACE
inhibitor-induced bronchospasm (16%) was not
significantly different from the
prevalence in patients on ACE inhibitors without an
adverse reaction (13%), P = 0.447. 6. The prevalence
of ACE inhibitor
cohort cough was 12.3% and 2.7% in the patients on
LLDs, P < 0.0001. Cough did not occur more commonly in
patients on
ACE inhibitors who had experienced any bronchospasm
(28%) than in patients on LLDs with bronchospasm
(27%).

ACE inhibitor-induced cough and bronchospasm.
Incidence, mechanisms and management                  
            
 Drug Saf 1996 Jul;15(1):72-8  Overlack A 
A dry, tickly and often bothersome cough is the most
common adverse effect of ACE inhibitors. Recent
studies indicate that
cough may develop in around 10% of the patients
treated with ACE inhibitors. In half of these
patients, the ACE inhibitor
has to be discontinued. Cough has emerged as a class
effect occurring with all ACE inhibitors with no clear
difference
between the single substances. While ACE inhibition is
safe in the vast majority of patients with obstructive
airways disease,
asthmatic symptoms or exacerbation of asthma as well
as a rise in bronchial reactivity have been
occasionally reported. ACE
inhibition increases the cough reflex. The mechanisms
underlying ACE inhibitor-induced cough are probably
linked to
suppression of kininase II activity, which may be
followed by an accumulation of kinins, substance P and
prostaglandins.
Physicians should be aware that a dry cough is the
most common adverse effect of ACE inhibitors and that
this symptom may
occur not necessarily shortly after institution of
therapy but months or even a year later. Replacement
by another ACE inhibitor
should not be tried, since the cough will almost
always recur on rechallenge with the same or another
ACE inhibitor. After
withdrawal of the ACE inhibitor, which is the
treatment of choice, cough will resolve usually within
a few days.

ACE-inhibitor-induced cough, an adverse drug reaction
unrecognised for several years: studies in            
                      prescription-event monitoring. 
Eur J Clin Pharmacol 1996;49(6):431-7   Kubota K;
Kubota N; Pearce GL; Inman WH 
OBJECTIVE. This study examines cough recorded in
Prescription-Event Monitoring (PEM) of four
ACE-inhibitors.
Particular attention was paid to the study of
enalapril because the drug was monitored before the
causal relationship between
cough and ACE-inhibitors had been widely accepted.
RESULTS. Several factors which had obscured the causal
relationship
in the individual cases were found to be also an
obstacle in PEM. For example, cough was a common and
non-serious event
and was under-reported in the PEM study of enalapril
and the rate was not strikingly different from that
recorded for other
drugs. Cough induced by ACE-inhibitors has several
characteristics which reduce the chance of a
recognisable "signal'. The
original questionnaires returned from doctors in the
PEM study of enalapril have been reexamined. The
observation that the rate
of cough diminished after enalapril had been stopped
rather than increased after starting, provided the
best evidence of
causality, because this was not affected by many
biases such as the publicity that had occurred prior
to doctors participating in
PEM completed later reports.

Higher incidence of discontinuation of angiotensin
converting enzyme inhibitors due to cough in black    
                                       subjects.  Clin
Pharmacol Ther 1996 Nov;60(5):582-8    Elliott WJ
OBJECTIVE: To compare the rates of discontinuation of
angiotensin converting enzyme (ACE) inhibitors in
patients with
different racial and ethnic backgrounds. METHODS: A
registry from a tertiary hypertension clinic
consisting of 892 patients
who received their first-ever dose of ACE inhibitor
therapy was examined. Surveillance for cough was
prospective,
systematic, and constant beginning in 1986 and
routinely included a trial of sinusitis therapy,
followed by withdrawal and
rechallenge before discontinuation of drug. RESULTS:
The prevalence (per 100 patients) of cough requiring
discontinuation of
ACE inhibitor therapy was 62 of 644 (9.6 per 100)
patients among black subjects compared with six of 248
(2.4 per 100)
patients among others (odds ratio, 4.0; 95% confidence
interval, 1.7 to 9.1; p < 0.001). There were no
significant differences in
discontinuation rates across the three most commonly
used ACE inhibitors: captopril (6.6%; all black
subjects), enalapril
(6.1%; 94% black subjects), and lisinopril (7.3%; 90%
black subjects). Cough was more common among women
(70% of
subjects). After adjustment (by backward stepwise
multiple logistic regression analysis) for baseline
differences, black subjects
had a relative risk of 2.58 (95% confidence interval,
1.21 to 4.65; p = 0.01) of discontinuation of ACE
inhibitor due to cough.
CONCLUSIONS: These data suggest that there may be a
race- or ethnicity-related difference in the
prevalence of cough
attributed to ACE inhibitor therapy. Although a
race-related difference in ACE gene polymorphism has
been suggested,
further work is necessary to define the biological
reason and pathophysiology for such a difference.

Delay of diagnosis and empiric treatment of
angiotensin-converting enzyme inhibitor-induced cough 
                                       in office
practice. Arch Fam Med 1995 Jun;4(6):525-8   Olsen CG 
OBJECTIVE: To evaluate the length of time taken to
diagnose cough due to the use of an
angiotensin-converting enzyme
(ACE) inhibitor and the frequency of interim diagnoses
and treatments given in an office practice. DESIGN:
Retrospective
case study. SETTING: Two academic group family
practice offices. PATIENTS: Seventeen solicited cases
of patients with
suspected or known ACE inhibitor-induced cough over a
2-year period. MAIN OUTCOME MEASURES: Documentation
in the patient chart of the nature and complaint of
the cough; the time between initiation of therapy with
the drug and complaint
of the cough; the time between initiation of therapy
with the drug and assessment of ACE inhibitor-induced
cough or
discontinuation of drug treatment; other diagnoses
given to explain the cough; and other treatments
given. RESULTS: There
was an average of 14.5 weeks between the initiation of
ACE inhibitor therapy and the first documentation of
the complaint of
cough, and an average of 24.0 weeks between the
initiation of ACE inhibitor therapy and documentation
of the cough side
effect. Physicians made several interim diagnoses
prior to recognizing cough as a side effect of ACE
inhibitor therapy.
Physicians prescribed 30 medications and took two
chest radiographs on seven patients experiencing ACE
inhibitor-induced
cough prior to recognition of this side effect.
CONCLUSIONS: The investigation found a significant
delay in making the final
diagnosis of ACE inhibitor-induced cough. Frequently,
physicians gave other diagnoses, ordered unnecessary
diagnostic tests,
and ordered treatments other than the discontinuation
of ACE inhibitor therapy. Earlier identification would
be more
cost-effective.


Angiotensin-converting enzyme inhibitors and cough: a
prospective evaluation in hypertension and in         
                            congestive heart failure. 
J Clin Pharmacol 1994 Nov;34(11):1116-20    Ravid D;
Lishner M; Lang R; Ravid M 
Angiotensin-converting enzyme inhibitors (ACE-I) have
become the mainstem of antihypertensive therapy and
first-choice
agents for vasodilatation in congestive heart failure
(CHF). A typical dry cough is the main cause for
discontinuation of ACE-I
therapy. Data about the incidence, course, and
clinical significance of this side effect are
conflicting. This study determined the
incidence of cough in ACE-I treated patients with
hypertension and with CHF and to appreciate its
clinical significance; 268
ACE-I treated patients, 164 with hypertension and 104
with CHF were prospectively followed for at least 1
year and
specifically questioned about cough and other side
effects. In those in whom cough developed, a second
and then a third
ACE-I were tried. Cough developed in 50 (18.6%) of the
268 patients; 23 patients with hypertension (14%) had
coughs 24.7
+/- 17.1 (SD) weeks after initiation of therapy; 27
patients with CHF (26%) had coughs 12.3 +/- 12 (SD)
weeks after the
start of ACE-I therapy (P = 0.005). All but three
patients had coughs also on the second and third
ACE-I. The time from the
beginning of therapy to the onset of cough was
significantly shorter with the second than the first
drug. ACE-I agents had to be
discontinued in 50% of the patients in whom coughs
developed, most of them in the CHF group. In the
others, cough was well
tolerated or disappeared during subsequent months. The
incidence of cough, which necessitated discontinuation
of ACE-I
treatment, was 4% among patients with hypertension and
18% among patients with CHF (P < 0.001)


Treatment of ACE inhibitor-induced cough.  
Pharmacotherapy 1999 Jul;19(7):804-10   Luque CA;
Vazquez Ortiz M 
Angiotensin-converting enzyme (ACE) inhibitors are
widely administered to treat numerous medical
conditions. Although
they are generally well tolerated, they are associated
with a dry cough that can lead to discontinuation of
treatment. Data
concerning the frequency, onset, and clinical effects
vary among the agents. When discontinuing the ACE
inhibitor is not an
ideal option, pharmacologic treatment of the cough may
be considered, such as cromolyn, baclofen,
theophylline, sulindac, and
local anesthetics.
Irene.

=====
Irene Campbell-Taylor, PhD
Clinical Neuroscientist

If one tells the truth, one is sure, sooner or later, to be found out.
Oscar Wilde.

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