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ΑΞΙΟΛΟΓΗΣΗ ΤΟΥ ΚΙΝΔΥΝΟΥ ΣΕ
ΦΑΡΜΑΚΕΥΤΙΚΗ ΠΑΡΑΤΑΣΗ ΤΟΥ QT
c
-
Baseline
Drug effect
D
~
ΠΑΝΑΓΙΩΤΗΣ ΚΟΡΑΝΤΖΟΠΟΥΛΟΣ
Επίκουρος Καθηγητής Καρδιολογίας
Α’ Καρδιολογική Κλινική Πανεπιστημίου Ιωαννίνων
Online Submissions: http ://www.wjgnet.com/esps/
.
wjc@wjgnet
:
. com
.
8462(on.line)
doi 10 4330 /wjc.v5.i6 175
.
Wo1ld
J Couiiol 2013[une 26; 5(6): 175-185
ISS 1949© 2013 Baisludeng. A.11
rights reserved
Mechanisms of drug-inducedproarrhythmiain clinical
practice
i
i
i i
i
l
Arkad a Konstantopoulou, Spyres Ts krikas, D m trios Asvestas, Panag otis Korantzopou os,
Konstantinos P Letsas
l
A
B
l
l
IKr b ockade
-=
I
2
1
APD prolongation
0
4
Activation of inward
depolarizaing currents (Ca++)
l
l
Norma APD
..---
-
-
-
-
-
-
---...
Pro onged APD
l
l
l
EADs
ECG
R
TDR
T
--
Q
Normal QT interval
s
..---
TdP
-
-
-
-
-
-
-
-
~
Prolonged QT interval
ΒΑΣΙΚΟΙ ΜΗΧΑΝΙΣΜΟΙ
ΕΠΙΚΤΗΤΟΥ ΜΑΚΡΟΥ QT - TdP
QT-pro
l onging
drug
INa-1a1e
c
-
Baseline
Drug effect
Roden DM. J Physiol 2016; In Press
Measurements of the QT-interval, examples of T-wave morphology, and Torsade de Pointes.
B
A
QT interval
II
D
E
Søren Fanoe et al. Eur Heart J 2014;35:1306-1315
I
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2014. For permissions please email: [email protected]
Europe
an
Short-long-short sequences
• “short-long-short” sequence (an extrasystole, followed a
by
post-extrasystolic pause) precedes the onset of TdP in
most
cases]. Thedelay
“short-long-short”
repolarization
which in animal sequence
models is provides
necessary
a
to
allow the late-plateau depolarizing currents (ICa-L
channel
and INa/Ca exchanger current) to initiate EADs
Two cases of drug-induced QT prolongation.
l
Patient A during treatment with 16 mg sertindo e (a B*
drug)
.
II
V2
V2
.
'
·
.·
Patient B during treatment
(a B*
: 180 mg:methadone
:
.: : .with
dru
_
II
~
RR =-1020 ms ,: .:"::
V2
::.' :.
L: l:
::;-!.':-
~ ~:
.
~_,......l
i" .:
QT= 500 ms (QTcB= 495 and QTcF = 497)
Patient B after methadone treatment had been ceased
II
,
V2
.:...1·:--..
_:..! ...;.:.
400 ms All
(QTcB
396 and QTcF
= 397)
Published on behalf of the European Society ofQT=
Cardiology.
rights= reserved.
© The
Author
2014. For permissions please email: [email protected]
Søren Fanoe et al. Eur Heart J 2014;35:1306-1315
QT = 4io ms
Europe
an
Heart
ΣΥΝΗΘΗ ΦΑΡΜΑΚΑ ΠΟΥ
ΣΧΕΤΙΖΟΝΤΑΙ ΜΕ ΠΑΡΑΤΑΣΗ QT
• Amiodarone
Cardiac drugs
• Sotal ol
i
• D sopyram
de
i
• Dofetilde
i
• Proca nam de
i
• Quin dne
i
• Se ect ve seroton n re-uptake nh b tors
i
esc tai opram, fluoxet ne
Antidepressants
l
i de
i
• Moclobem
i
:
l
• Tr cyclic ant depressants*
i
• Lithum
l
i
• Am su pr dei
Anti psychotics
• Ch orpromaz
ne
i
i do
• Haloper
• Z pras
i done
• Th or
i dazl ne
i ne
• Loratad
l
• Astem zoe
i
• D phenhydram ne
i
• Cl profloxac n,
mox floxac n,
sparfloxacin
i
• C ari thromycin, erythromycin
Antihistam nes
Antimicrobias
• F uconazo
i
i e,
i
• Pentam d ne
i
Other drugs
voriconazo e
i
• Ch oroqu ne
i
l
i
i
l
i
i
i
i
cita opram,
i
i
Πόσο συχνή είναι η φαρμακευτική
παράταση του QT ?
• The incidence of drug-induced TdP in the
general
population is unknown
• In a survey in United Kingdom and Italy,
noncardiac
agents that have pro-arrhythmic potential (defined as
QT interval prolongation or TdP) represented 3% and
2% of total prescriptions in both countries, respectively
Πόσο συχνή είναι η εμφάνιση TdP σε
φαρμακευτική παράταση του QT ?
•
•
•
The exact incidence of drug-induced TdP in the general
population is unknown
QT-prolonging antiarrhythmic drugs such as quinidine, dofetilide
and sotalol cause torsades de pointes in 1–5% of exposed
subjects (Abraham et al. 2015)
By contrast, antibiotics, antipsychotics and other classes of
‘non-cardiovascular drugs’ associated with diLQTS risk produce
torsades de pointes at much lower frequencies
(e.g.1/1,000,000 exposures)
D
Amlsulpride overdose
N
••
••
tO
101
120
He;1r1 Ra1, tbpm)
144
1Ct
TdP
E"UrtOPEAN
SOCIETYOF
CARDIOUXiY ll
Europace (2014) 16, 101108
doi:10.1093/europace/eut214
- ..
.
CLINICAL R ESEARCH
Channelopathies
Epidemiology of symptomaticdrug-induced long
QT syndromeandtorsade de pointes in Ge
rmany
Giselle Sarganas1, Edeltraut Garbe1•2•3, Andreas Klimpel1, Rolf C. Hering 1,
Elisabeth Bronder 1,and Wilhelm Haverkamp4*
Using a Berlin-wide network of 51 collaborating hospitals 180 clinical
departments), adult patients presenting with long QT synd rome
(LQTS/TdP) between 2008 and 2011 were identified by a ctive surveillance
of these hospitals.
While European annual reporting rates based on spontaneous reports
suggest an annual diLQTS/TdP incidence of 0.26 per mil ion in Germany,
we estimated a considerably higher incidence of diLQTS/TdP in an active
surveillance approach.
The age-standardized incidence of diLQTS/TdP in Berlin was estimated to
be 2.5 per million per year for males and 4.0 p r million per year for
females.
ΠΩΣ ΜΕΤΡΟΥΜΕ ΤΟ
QT Διάστημα ?
Methods in Clinical
Pharmacology Series
n each lead of the ECG using a clear measuring ruler
1 Measurement: The QTi nterval is measured
i
i or by count ng the small squares on the ECG
is 25 paper when the
i paperi rate
i
il
i li
.
mm
s1•
The
QT
ntervali s measured from the beg
(isoelectr c ne)
2 ECG
: nning of the Q wave unt the T wave returns to the baseline
• Thrleads: The
l
:QT is measured n a total of six leads including
ee
limb
eads
I, II and usually
• Thr
l
.
i aVF or aVL Lead Ill is often lowi voltage and difficult i to measure. and aVR
i is inverted. .
3 Mediee chest eads V2, V4 and V6 1f lposs ble, although V3. and VS may be used f there is a poor tracing n these leads V1 is d fficult to measure
4 Heartan QT: The median of the six individua leads is then calculated
.
rate:
The
heart
rate
can
be
taken
from
the
ECG
machine's
automated
readout
and
is
an
average
measure
of
the
RR
interval
for the 12-lead ECG
5 Abso
i
i
6 QT nlute QT interval: Only the absolute QT nterval s used and not the QTc or any
. correction of the QTi interval. li
thereomogram: The QT is plotted against the heart rate on the QT nomogram (Figure 2) If the QT-heart rate pair s above the ne on the nomogram
it is abnormal and
is an increased risk of TdP.
Tή
ΑΥΤΟΜΑΤΗ ΜΕΤΡΗΣΗ
«Με το χέρι» ?....
Automated versus Manual Measurem
Interval and Corrected QT Interval
ent of t he QT
. .
Yuji Kasamaki,
M.D.,*
Yukio Ozawa,
M D *
Masakatsu , . .
, . ,
Akira Sezai M ,D ,t Takashi
Yamaki B .,A ,+
Mutsuo
,
Ka
, .
Ichiro Watanabe M.D. * Atsushi
Hirayama M.D.,*
.
and Tomohiro Nakavarna M D ~
Ohta,
M.D.,
neko,
Ph.D.,
mated
he QTc
Man versus Machine: Comparison of Auto
and Manual Methodologies for Measuring t
. : A Prospective
.
ty, M.S.J
Interval
Study .
ORIGINAL ARTICLE
·
Jean T Barbey, M.D ,* Margaret Connolly,
Bea
and Mori
M.D.§
J.
Krantz,
Ph D.,t Brenda
*
+
VOLUME 38: NUMBER 1 : FEBRUARY 015
2
ARTICLE
Risk assessment of drug-induced
QT prolongation
Table 2
Step by step approachfor using the QT nomogramto determine if a QT interval is abnormal 1
Steps
Obtain ECG
Approach
The QT interval length is manually measured in 6 leads on the ECG, usually:
• 3 limb leads: I, II and aVF
• 3 chest leads: V2, V4 and V6
Measure the
absolute
QT interval
The QT interval is manually measured from the start of the Q wave until the T wave returns to baseline
On a standard ECG at 25 mm per second this is best done by counting the number of small squares
• 5 small squares= 200 milliseconds
• 8 small squares= 320 milliseconds
Do not use the ECG automated readout or QTc
Calculate the
median QT
The median is the middle number of all 6 measured QT intervals when arranged in numerical order
Determine
heart rate
The heart rate is the average measurement derived from the RR interval on the 12 lead ECG and is most accurate when read
from
an automated ECG
The median QT length is then plotted against the heart rate on the QT nomogram (Fig. 4). If the QT-heart rate pair is above the line
on
the nomogram it is a prolonged QT and there is an increased risk of torsades de pointes.
Plot on QT
nomogram
If there are 2 middle numbers, e.g. position 3 and 4, then the average of these 2 measurements is the median
ΜΕΘΟΔΟΙ ΣΤΗ ΜΕΤΡΗΣΗ
ΤΟΥ QT ΔΙΑΣΤΗΜΑΤΟΣ
01
z 3H luJ
Oh I• z ,,3 (uJ
Oh fr • C2,t Cu)
1)
1)
ii
'r~----::-::.;.--J1)
waveform ( x2
·1
PB$
=
P~
OU
• IU Cul
• U Cul
Aft r,,1
Baseline
Tangential line
Noise level
ΜΕΘΟΔΟΣ ΤΗΣ ΕΦΑΠΤΟΜΕΝΗΣ
ΔΥΣΚΟΛΙΕΣ ΣΤΗ ΜΕΤΡΗΣΗ
ΤΟΥ QT ΔΙΑΣΤΗΜΑΤΟΣ
Drifl.
keletal
mu de
T ,u, e endpoint?
potential noi e
T wave endpoint?
/I
LO\\
amplitude
T wave endpoint?
If the T wave and the U wave did not merge, or fuse, then the QT
segment would not include the U wave.
Πόσο εύκολα αναγνωρίζεται η
παράταση του QT στην κλινική πράξη?
Correct classification of the QT
interval
either “long” or “normal” was
achieved
as
by
96% of QT experts and 62% of
arrhythmia experts, but by
less than 25% of cardiologists and noncardiologists. Viskin S, et al. Heart Rhythm 2005; 2: 569-574
Υπολογίζουμε το QTc ?
Preferred QT Correction Formula for the Assessment of
Drug-Induced QT Interval Prolongation
.
. M O.,
JOHN CHILADAKIS, M.O., F.E S. .C., ANDREAS KALOGEROPOULOS
. .
PANAGIOTIS ARVANITIS, M.O., NIKOLAOS KOUTSOGIANNIS,
M O . FANT.
.
.
ZAGLI. M O., and OIMITRIOS ALEXOPOULOS.
M O., F.E.S.C.,
F.AC.C.
From the Cardiology Department, Patras University Hospital. Patras.
Greece
Drug-Induced QTc Interval
Assessment.
Introduction: There is debate on the optimal QT correc•
tion method to determine the degree of the drug-induced QT interval prolongation in relation to heart rate
(AQTc).
Methods: Forty-one patients (71 ± 10 years) without significant heart disease who had baseline normal
QT interval with narrow QRS complexes and had been implanted with dual-chamber pacemakers were
subsequently started on antiarrhythmlc drug therapy, The QTc formulas of Bazett, Fridericia, Framing•
ham, Hodges, and Nomogram were applied to assess the effect of heart rate (baseline, atrial pacing at
60 beats/min, 80 beats/min, and 100 beats/min) on the derived AQTc (QTc before and during
antlarrhythmlc therapy).
Results: Drug treatment reduced the heart rate (P < 0.00 I) and increased the QT interval (P < 0.00
I). The heart rate increa e hortened the QT interval (P < 0.001) and prolonged the QTc interval (P <
0.001) by the u e of all correclion formulas before and during antiarrhythmic therapy. All formulas gave
at 60 beats/min imilar AQTc of 43 ± 28 ms. At heart rates slower than 60 beats/min. the Bazett and
Framingham
methods provided the most underestimated AQTc values (14 ± 32 ms and 18 ± 34 ms, respectively). At
heart rates faster than 60 beats/min, the Bazett and Fridericia methods yielded the most overestimated
.
AQTc values, whereas the other 3 formulas
gave similar AQTc increases of 32 ± 28 ms.
Conclusions: Bazett's formula should be avoided to assess AQTc at heart rates distant from 60
beats/min.
The Hodges formula followed bv the Nomogram method seem most a ro rlate in assessing AQTc.
(J CardiovascElectrophysiol,Vol. 21, pp 905-913, August 2010)
ΠΟΙΟ ΕΙΝΑΙ ΤΟ ‘ΟΡΙΟ
ΕΠΙΚΙΝΔΥΝΟΤΗΤΑΣ’ ΣΤΗΝ
ΠΑΡΑΤΑΣΗ ΤΟΥ QT ?
• The majority of drug-induced TdP
occur with QTc values of more than
• 500 ms
Συνεχώς αναγνωρίζεται η κλινική αξία
του Heart rate – QT interval
nomogram / Τιμές πάνω από τη
γραμμή υποδηλώνουν υψηλό κίνδυνο
TdP
The nomogram line separates HR,QT pairs above
the line associated with an increased risk of
torsades de pointes compared with those below
the line
QT nomogram
-
500 . . . .
I
I
I
iii
I
I
I
I
i iii
I
i
....
:_fil
I
I
I
I
I
I
I
I
I
iii i
I
I
I
.... ..
I
I
I
I
I
I
..
I
The QT nomogram had a
sensitivity of 97% and
specificity of 99%
….compared with
I
iii l l l l l l i ii
- ri--i--r--·-rtti-- --lrtr ITTtl1
Bazett’s formula with a
:
VI
-
E
400
l•
i
: : : :
: : : :
: : : :
! ! ! !
! ! ! !
! ! ! !
I
o
I
I
I
: : : :
:
:
:
:
---:--1--1--t-·
I
I
I
I
: : : :
:
I
I
I
I
! !
4
0
I
I
I
:
:
f".i...._
l ! ~::
!
!
!:
!
I
I
I
! !! !
: : : :
: :,•
: : : :
: : : :
: :: :
-·t-·t-·:----:--- --1--1-·t--~·1;:-:-----:--1-·t-·! --:---:---:--1-I-- -:---:---:--1---:----:---:---:-:
:
:
11
11
300
20
0 2
0
: :
: : : :
llll ~rri--r-- rrti--
60
80
Heart rate
:
:::
10
0
:
12
0
(beats min'")
~:: ~: L ~
:
14
0
16
0
:
:
sensitivity of 99% and
specificity of 67%
BTCP BrtUsh Journal of
Pirtor to eommencemene,
Methods in Clinical
Pharmacology Series
obtain a :basenne ECG. Ideally
oo[tert ECCs: at dlll'Eerent ttrne
pe!!rlod!s: or a. 14 h I l·faad
Holter assessment
:.,
Clinical
Pharmacolog
y
Mam!lalty measure
tln.e QT fnterval as
ou:Ufned lnla'lble 2
Plot the, QT-heart
rate pa.l'r on the QT
nomogram
IUhe QT-hMrt rate pairr Is:
below the nomogram line, t:hen
commence the imedtc-atlon.
lftl!!.e Q'f..heart rate pair Is
a0011e the mmnogram llm.l!!!,con,!.fder
other m.ed:ieatlonst.hau are n.-0t
known lio prolom.g tl1u11 QT
tntterval
Obtain repe.a!t ECG,s.afiter
commencement and ini,. plot
the Q"'Uleart rate pair on
the n.omogram
Uthe. QT-hH'.rt rate pair
remarns lbe'tow the
nomogram llne,,,mnttnue
tln.e moolcadon.
Cons:lder discon~mlingthe
11111Led:Ul:'atlon If the Q1=41eart
rat-'! pair
tis aboY,e
uh.e rn,ol!DOHra.mllme
ΑΡΚΕΙ Η ΜΕΤΡΗΣΗ ΤΟΥ QT ?...
ΔΙΑΣΠΟΡΑ/ΕΤΕΡΟΓΕΝΕΙΑ
ΕΠΑΝΑΠΟΛΩΣΗΣ?
• Drugs such as amiodarone prolong QT interval
with minimal TdP risk (due to homogeneous
prolongation of repolarization)
• An increased transmural dispersion of
repolarization (TDR) is probably the best
predictor of TdP
• The TDR can be measured indirectly using novel
ECG markers, such as the Tpeak-end interval
and the Tpeak-Tend/QT ratio.
• T wave alternans
World Journal of
Cardiology
World J Catdiot 2013 July 26; 5(7): 242-246
Online Submissions :http / :/www.wjgnet.com/esps/
wjc@wjgnet com
.
doi:10.4330 / wjc.v5.i7.242
ISSN 1949-8462 (on.line)
© 2013 Baishideng .All rights reserved .
Ibutilide and novel indexes of ventricularrepolarization in
persistent atrial fibrillationpatients
i i s Korantzopou
l os, Konstant
i
i Kots a,i Giann s Baltogiannis,
i l
Panagot
nos P Letsas, Anna
Kallirro Ka antz ,
Konstantinos Kyrlas, John A Goudevenos
Table 2 Electrocardiographic variables before and after
ibutilide infusion
Variable
s
Before
ibutilide
QTc (ms)
442 ± 29
Tpe in lead II (ms)
79 (70-88)
Tpe in precordial leads (ms)
96 (80-108)
25 (23-30)
Tpe dispersion (ms)
0.22 (0.18-0.24)
Tpe/ QT in lead II
Tpe/QT in precordial leads 0.23 (0.18-0.26)
After
ibutilide
Pvalu
e
471 ±37
0.037
100 (87-104) < 0.001
101 (91-119)
0.021
35 (27-39)
0.012
0.24 (0.22-0.28) 0.12
0.26 (0.23-0.28) 0.028
i
ΠΑΡΑΓΟΝΤΕΣ ΚΙΝΔΥΝΟΥ….
• Ηλεκτρολυτικές διαταραχές π.χ. υποκαλιαιμία
υπομαγνησιαιμία, υποασβεστιαιμία
• Συγχορήγηση QT prolonging drugs
• Βραδυκαρδία – παύσεις
• Εκτακτοσυστολική αρρυθμία
• QT short term variations / T wave alternans
• Genetic variations, mutations
• Δομική καρδιοπάθεια
• Προχωρημένη ηλικία
• Θήλυ Φύλο
• Digoxin, Diuretics
ΦΑΡΜΑΚΕΥΤΙΚΗ ΠΡΟΦΥΛΑΞΗ
ΑΠΟ Drug-induced QT prolongation
Έχει κάποιο ρόλο η χορήγηση Μαγνησίου ?
Effect of High Doses of Magnesium on Converting lbutilide to a
Safe and More Effective Agent
, i N kolao Kafka .
Sotirio Patsilinako . M03, Apo tolo Chri tou, MDa.,:,
.
i 3, Spyr don .Kat
MDb ikolao
ikolaou, M03, Dionysio Antonatos
M0
i
ano MDb.
Stavros Spanod mo , MD3, and Dirnitrio Babali .
MDb
Ventricular arrhythmias
Variable
onsustained ventricular tachycardia
Sustained ventricular tachycardia
Torsade de pointes
Total ventricular arrhythmias
lbutilide Alone
(n = 229)
13(1.3%)
6 (2.2%)
8 (3.9%)
17 (7.4%)
Magne ium Plus Ibutilide
(n = 247)
p Value
2 (0.8%)
I (0.4%)
0(0%)
3(1.2%)
0.93
0.11
0.009
0.002
Of the patients in groups A and B, 154 (67.3%) and 189 (76.5%), respectively, were converted to SR
(p 0.033). arrhythmias (sustained, nonsustained ventricular tachycardia, and TdP) occurred
Ventricular
significantly more often in group A than in group B (7.4% vs 1.2%, respectively, p 0.002).
Am J Cardiol 2010;106:673– 676
Prevention of drug-induced TdP
•
•
•
•
•
Βασικό ΗΚΓ, εργαστηριακός έλεγχος
Διερεύνηση παραγόντων κινδύνου
Benefit-Risk balance on an individual basis
Αποφυγή συγχορήγησης 2 QT prolonging drugs
Έναρξη φαρμάκου στη χαμηλότερη δόση –
προσεκτική τιτλοποίηση – minimal duration
• ΝΟΜΟΓΡΑΜΜΑ – Επανεκτίμηση μετά την έναρξη
του φαρμάκου/ Νέο ΗΚΓ
• Παρακολούθηση ηλεκτρολυτών σε high-risk
ασθενείς(π.χ. δομική καρδιοπάθεια, διουρητικά)