Use of venlafaxine compared with other antidepressants and the risk of sudden cardiac death or near death: a nested case-control study
BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c249 (Published 05 February 2010) Cite this as: BMJ 2010;340:c249
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A research article on Cardiovascular effects of high dose venlafaxine
XL in patients with major depressive disorder by
Patrick Mbaya 1 *, Faouzi Alam 1, Sindhu Ashim 1, David Bennett 2 showed
that on high dose venlafaxine (mean 346.15 mg; range 225-525 mg) did not
show any clinical significant effects on electrocardiogram (ECG)
parameters including PR, QT, QRSD and QTc interval
According to the summary of Nicola pocock from the National Electronic
Library for medicine, David Taylor, Chief Pharmacist at the South London
and Maudsley NHS Foundation Trust) concludes that “for now, continued
restriction on the use of venlafaxine on the grounds of cardiovascular
toxicity seems inappropriate”.
References
1)National Electronic Library for medicine
2)Intersciences
1Department of Psychiatry, Laureate House, South Manchester University
Hospital, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK
2Department of Cardiology, South Manchester University Hospital,
Wythenshawe Hospital, Wythenshawe, Manchester, UK
Competing interests:
None declared
Competing interests: No competing interests
Martinez and colleagues [1] having compared rates of reported sudden
cardiac death or near death in takers of antidepressants using the General
Practitioner Research Database draw the reasonable conclusion that no
excess risk is likely to attach to the taking of venlafaxine, a selective
serotonin reuptake inhibitor [SSRI] and nor-adrenaline reuptake inhibitor,
compared with dosulepin, a tricyclic antidepressant and fluoxetine and
citalopram, both SSRIs. The findings have led them to suggest in the
printed summary version that “at pharmacological doses venlafaxine does
not increase risk of life threatening arrhythmias”. This conclusion being
derived from a no-inferiority comparison with other drugs is unjustified
because the results are compatible with raised risk for all these agents.
The writer of your editorial [2] asks for more information from
studies of arrhythmias and sudden death in humans. Since his cited review
two years ago [3] Kranz et al [4] have reported an association between
adverse events and combined anxiolytic and antidepressant treatment, Whang
et [5] al have reported a tripling of risk of sudden cardiac death in the
Nurses Health Study in individuals taking antidepressants [mainly SSRIs],
and we have found a doubling of risk of sudden death in takers of SSRIs
[6].
All studies necessarily being observational it is difficult to be
sure that factors other than the antidepressant are not responsible for
these findings [7]. However, given the consistency of the information,
failure to account for the results through other social or disease-related
factors, and the existence of a plausible mechanism in interference with
cardiac conduction there has to be strong suspicion that sudden death in
takers of antidepressants, whether tricyclic or SSRI, is both treatment-
associated and caused.
1. Martinez C, Assimes TL, Mines D, Dell`Aniello S, Suissa S. Use of
venlafaxine compared with other antidepressants and the risk of sudden
cardiac death or near-death: a nested case-control study. BMJ
2010;340;c249.
2. Taylor D. Venlafaxine and cardiovascular toxicity BMJ
2010;340:c411.
3. Taylor D. Antidpressant drugs and cardiovascular pathology: a
clinical overview of effectiveness and safety. Acta Psychiatr Scand
2008;118:434-42.
4. Kranz DS, Whittaker KS, Francis JL et al. Psychotropic medication
usage and risk of adverse cardiovascular events in women with suspected
coronary artery disease: outcomes from the Women`s Ischemia Syndrome
Evaluation (WISE) study. Heart 2009;95:1901-6.
5. Whang W, Kubransky ID, Kawachi I et al. Depression and risk of
sudden cardiac death and coronary heart disease in women. J Am Coll
Cardiol 2009;53:950-8.
6. Jolly K, Gammage MD, Cheng KK, Bradburn P, Banting MV, Langman MJ.
Sudden death in patients receiving drugs tending to prolong the QT
interval. Br J Clin Pharmacol 2009;68:743-51.
7. Jolly K, Langman MJS. Psychotropic medication: curing illness or
creating problems? Heart 2009;95:1893-4.
Competing interests:
MJSL has been an advisor to Merck and Co Inc, Galpharm, and Procter and Gamble.
Competing interests: No competing interests
Martinez et al [1], in their robust study, provide evidence that
therapeutic use of venlafaxine is as safe as use of 2 other SSRIs and low
dose dosulepin [2]. Although they acknowledge the limitations associated
with the use of GPRD, but a major aspect still does spring to mind i.e.
the average therapeutic dose of SSRIs and Venlafaxine has not been
specified. We do know that the therapeutic dose range of venlafaxine can
vary from 150mg/day to up to 375 mg/day.
This is important and relevant to the implications that can be drawn
from this study. Firstly, patients may have received lower doses of
venlafaxine as they were being managed in the primary care wherein the GPs
would have tended to consider the lower range of therapeutic dose than the
higher range; especially keeping in view that the data is from 1995
onwards when venlafaxine was initially introduced in the UK. This
assumption is based on the aspect that no information is available
regarding initiation and/or monitoring of these patients by secondary care
clinicians. Secondly, it is known that there is a dose-dependent effect
with venlafaxine i.e. at higher therapeutic doses it tends to act more on
the adrenergic system than the serotonergic system leading to an increase
in heart rate and blood pressure [1,2]. Such dose-dependent effect is not
seen with SSRIs as they have a tendency to display a flat dose-response
curve which may imply that at higher therapeutic doses, the frequency of
cardiac side effects should not be pronounced. This would be expected
intuitively anyway as SSRIs have minimal effect on adrenergic system in
comparison to venlafaxine [3].
Additionally, dosulepin, though linked with cardiotoxicity [1] and
effects on the adrenergic system, was used in sub-therapeutic doses. Hence
the confidence that can be placed on the result that venlafaxine is
comparable to dosulepin (in terms of risk of sudden cardiac death) is
weakened. Taylor [2] probably endorses my viewpoint in his editorial
(Column 1, Para 3, Lines 8-13). Hence, it may useful to re-visit the
clinical data in terms of comparable therapeutic dosage regimes of
venlafaxine and a prototypical tricyclic antidepressant [TCA] (i.e.
dosulepin, amitryptiline, imipramine). This may not be that easy keeping
in view the increased usage of SSRIs and fall in that of TCAs over the
last 15 years or so; especially also since the availability of NICE
guidance [4].
Based on my PUBMED search, it is interesting to note that extremely
few prospective post-marketing studies have been carried out/reported in
evaluating cardiac related adverse events in people who are prescribed
venlafaxine with pre-existing hypertension or cardiac problems (or who
develop such events following venlafaxine initiation) i.e. the ‘at-risk’
population. ONE WONDERS WHY! This may be due to various factors; not
discounting the ethical aspects of carrying out case-control studies in
such population. Personally, in my clinical practice, I have not
encountered any major adverse event with venlafaxine in this ‘at-risk’
population.
I would endorse Taylor’s view [2] that we require evaluation of
meaningful outcomes. Hence, another way of addressing the concerns around
risk with use of venlafaxine would be by conducting well-designed,
longitudinal studies in high/at-risk human population (i.e. patients with
hypertension and cardiac problems) with clearly defined outcome measures.
Till then the current advice of UK regulatory authorities would
persist, and continue to deprive many appropriate ‘at-risk’ patients of an
effective antidepressant like venlafaxine.
REFERENCES
[1] Martinez C, Assimes TL, Mines D, Dell’Aniello S, Suissa S. Use of
venlafaxine compared with other antidepressants and the risk of sudden
cardiac death or near death: a nested case-control study.n BMJ 2010; 340:
c249.
[2] Taylor D. Venlafaxine and cardiovascular toxicity. BMJ 2010; 340:
c411.
[3] Sadock BJ, Sadock VA. Comprehensive Textbook of Psychiatry-7th
Edition. Lippincott Williams & Wilkins, 2000.
[4] National Institute for Clinical Excellence. Clinical Guideline 23
for Managing Depression. NICE, December 2004.
Competing interests:
None declared
Competing interests: No competing interests
Venlafaxine and ‘At-Risk’ Population: The need for more evidence-based research!
We thank Dr Gupta for his letter
on the potential effects related to the studied doses of antidepressant
medications. Here we provide additional dosing information about venlafaxine
and dosulepin to facilitate interpretation of the venlafaxine/dosulepin contrast.
The distribution of daily doses
of dosulepin and venlafaxine prescribed in our control patients, stratified by
age appear in Tables 1a and 1b. In the
is 75 mg daily and between 50 to 75 mg daily in the elderly. [BNF 58 Sep 2009]
Table 1a: Daily dosulepin and
venlafaxine dose of controls at index day by age group
mg/daily
Dosulepin
Age <_65 xmlns:yearso="urn:x-prefix:yearso" yearso:p="yearso:p"/>
n (%)
Dosulepin
Age ≥ 65 years
n (%)
Venlafaxine
Age <_65 xmlns:yearso="urn:x-prefix:yearso" yearso:p="yearso:p"/>
n (%)
Venlafaxine
Age ≥ 65 years
n (%)
<_50 mg="mg" d="d" span="span"/>
27(16.2)
220(26.0)
5(3.5)
40(10.0)
≥50 to <_75 mg="mg" d="d" span="span"/>
29(17.4)
205 (24.3)*
0
3(0.8)
=75 mg/d
49 (29.3)
276 (32.7)
55(38.7)
212(52.7)
>75 to
1(0.6)
0
0
0
≥100 to
12 (7.2)
36(4.3)
4(2.8)
13(3.2)
≥150
41 (24.6)
64(7.6)
69(48.6)
117 (29.1)
Missing
8(4.8)
44(5.2)
9(6.3)
17(4.2)
* Minimum effective dose in
depression
Table 1b: Daily fluoxetineand citalopram dose
of controls at index day by age group
mg/daily
Fluoxetine Age <_65 xmlns:yearso="urn:x-prefix:yearso" yearso:p="yearso:p"/>
n (%)
Fluoxetine Age ≥ 65 years
n (%)
Citalopram Age <_65 xmlns:yearso="urn:x-prefix:yearso" yearso:p="yearso:p"/>
n (%)
Citalopram Age ≥ 65 years
n (%)
<_20 mg="mg" d="d" span="span"/>
7 (2.2)
27 (2.8)
23 (12.2)
235 (26.4)
≥20 to
251 (79.4)
834 (86.4)
126 (66.7)
549 (61.7)
=40 mg/d
45 (14.2)
46 (4.8)
28 (14.8)
72 (8.1)
>40 to <_60 mg="mg" d="d" span="span"/>
0
0
1 (0.5)
2 (0.2)
=60 mg/d
2 (0.6)
2 (0.2)
5 (2.7)
9 (1.0)
≥60 mg/d
0
0
0
0
Missing
11 (3.5)
56 (5.8)
6 (3.2)
23 (2.6)
In our study the
mean±SD dosulepin dose on the index day (in controls) was 86.7 ± 50.5 mg/day in patients younger than 65 and 63.7 ±
37.1 mg/day in patients≥65 years. Overall, 33.6% of dosulepin patients younger than 65 and
26.0% of dosulepin patients ≥65 were prescribed
sub-therapeutic doses. The mean±SD daily dose of venlafaxine (control
patients) was 110.7± 64.2 on the index day. Overall, 8.8% of venlafaxine
controls patients received less than the minimum recommended therapeutic dose
of 75 mg/day. Contrary to Dr Gupta’s expectation, sub-therapeutic dosing of
dosulepin was actually more common than for venlafaxine. That venlafaxine
showed no elevated risk of sudden cardiac death or near death compared with
dosulepin under these circumstances argues for the robustness of our findings.
Dr Gupta is correct that GPRD is
limited to information on prescribing by GPs. Given the limited access to
secondary psychiatric care in the
with depression are initially treated by their GP. Some patients may be seen by
a psychiatrist who would issue the first prescription and determine the daily
dose or dose regimen. Subsequent prescriptions would then be issued by the GP.
We agree with Dr Gupta that specialists, who care for more severely ill
patients, are likely to prescribe antidepressants at doses higher than GPs.
We agree with Dr. Gupta’s observation that very few studies
have addressed the cardiac safety of venlafaxine
specifically in populations at high risk for cardiac events. We suspect that
even using large population-based cohorts, such studies in the ‘at-risk’
subpopulation would have limited power, a function of the smaller size of this
subpopulation, the low number of venlafaxine-exposed
patients in the subpopulation and low incidence of study outcomes (e.g., sudden
cardiac death).
References:
Rapid Responses published: Nitin Gupta (15 February 2010)
Venlafaxine and ‘At-Risk’ Population: The need for more evidence-based
research!
British Medical Association, Royal
Pharmaceutical Society of
No 58 (Sepember 2009).
BMA, RPS, 2009.
Competing interests:
DM is a employee of Wyeth and owns company stock options. SS has participated in advisory board meetings, conferences, and participating as a speaker in scientific meetings by various companies (AstraZeneca, Boehringer Ingelheim, Glaxo SmithKline, Pfizer, and Sepracor) and SS received research grants from AstraZeneca, Wyeth, and GlaxoSmithKline. TA, SD, and CM have nothing to declare.
Competing interests: No competing interests