com
Heart 2000;84:339346
A
ll drugs currently marketed for the treat- ter understood and less variable among patients.
ment of arrhythmias were developed in Thus, for example, sodium channel blocking
the absence of knowledge of the specific drugs with slow onset and oVset kinetics of block
molecules the drugs target to achieve their (the class Ic (and to a lesser extent Ia)
therapeutic and adverse eVects. Nevertheless, eVect, seen with flecainide) are likely to produce
combining the characterisation of drug eVects conduction slowing at normal rates and the
in vitro and in whole animal models with stereotypical set of toxicities, described below
medicinal chemistry approaches to modify (proarrhythmia: sodium channel block). As our
existing molecules has led to new compounds understanding of the molecular basis of these
with related pharmacologic actions derived and other proarrhythmia syndromes (and in-
from older drugs (for example, procainamide deed arrhythmias in general) evolves, it seems
begat flecainide). It has thus been natural to likely that drugs exerting antiarrhythmic eVects
group drugs with common mechanisms of yet lacking the potential to cause serious toxicity
action. This approach can be useful for the cli- may be developed.
nician to the extent it allows prediction of a The Sicilian Gambit proposed an alter-
patients response to a given drug. One widely nate approach to classifying antiarrhythmic
used scheme is that popularised by Vaughan drug actions.2 In this scheme, the arrhythmia
Williams in which drugs are subdivided into mechanism assumes primacy, and antiarrhyth-
four broad classes.1 The Vaughan Williams mic drugs (or other treatments) are then classi-
classification has been criticised because many fied by the way in which they interact with
drugs fall into multiple classes (table 1): quini- arrhythmogenic triggers or substrates to sup-
Correspondence to: dine both blocks sodium channels and pro- press arrhythmias. A near trivial example is
Dan M Roden MD,
Director, Division of
longs action potentials (class I + III), while macroreentry based on the presence of a
Clinical amiodarone blocks sodium channels, exerts bypass tract. Understanding this mechanism
Pharmacology, antiadrenergic actions, prolongs action poten- then allows the clinician to select drugs that
Vanderbilt University tials and QT intervals by blocking potassium target the portion of the circuit at which phar-
School of Medicine, channels, and blocks calcium channels (classes macologic interruption is most likely (the AV
532C Medical Research I + II + III + IV, respectively).2 3 Moreover, node) or target the circuit by ablation of the
Building-I, Nashville,
TN 37232-6602, USA
both compounds exert other important phar- accessory pathway. The identification of such a
email: Dan.Roden@ macologic actions, such as inhibition of specific vulnerable parameter in an arrhythmia
MCMail.Vanderbilt.edu pathways of drug elimination (both), block- mechanism should, in theory, allow develop-
ade with vasodilation (quinidine), and inter- ment of entirely new approaches to treatment.
K+ channel block
Na+ channel block (I*) (III)
At all Predominantly Other K+ Ca2+ channel -blockade Other clinically important autonomic or
rates at fast rates IKr channels block (IV) (II) electrophysiologic actions (all )
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Atrial flutter
Mortality Exacerbation of with 1:1 AV Torsades de Brady- Exacerbation of
post-MI sustained VT conduction pointes arrrhythmia heart failure Other clinically important adverse eVects
Adenosine (transient)
Amiodarone Rare Pulmonary fibrosis
Photosensitivity
340 Corneal microdeposits
Cirrhosis
Neuropathy
Hypotension (IV)
Blockers (acute) Bronchospasm
Altered response to hypoglycaemia
Bretylium Hypotension
Calcium channel blockers Constipation (verapamil)
(verapamil, diltiazem)
Digitalis Arrhythmias
Altered mentation, vision
Nausea
Disopyramide Constipation
Urinary retention
Glaucoma
Dry mouth
Dofetilide
Flecainide
Ibutilide
Lidocaine Altered mentation
Seizures
Mexiletine Nausea
Tremor
Moricizine
Procainamide Drug induced lupus (arthritis, rash,
occasional pericarditis)
Nausea
Hypotension (IV)
Marrow aplasia
Propafenone Occasional Bronchospasm (especially in PMs)
Quinidine Diarrhea
Nausea
Sotalol Bronchospasm
Tocainide Nausea
Marrow aplasia
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relevance in clinical management. These in- ing agents, empiric administration of magne-
clude proarrhythmia syndromes discussed sium regardless of serum magnesium, correc-
below and other important adverse eVects pre- tion of serum potassium to 4.55 mEq/l, and
sented in table 2 as well as pharmacokinetic manoeuvres to increase heart rate (isoprenaline
properties presented in table 3. (isoproterenol) or pacing) if necessary. Long
term management of patients with QT prolon-
gation on a congenital or even acquired basis
Proarrhythmia: torsades de pointes usually relies on blockers, although in some
cases pacemakers or implantable cardioverter
defibrillators (ICDs) are advocated.
Torsades de pointes is estimated to occur in
18% of patients exposed to QT prolonging
antiarrhythmics: sotalol, quinidine, dofetilide,
Proarrhythmia: sodium channel block
and ibutilide fall into this category. While this
reaction is generally viewed as unpredictable,
certain risk factors can be identified: female sex, The first drugs used to suppress cardiac
underlying heart disease (particularly congestive arrhythmias were quinidine, procainamide,
heart failure or cardiac hypertrophy), hypokalae- and lidocaine, which share the common prop-
mia, and hypomagnesaemia. In patients receiv- erty of sodium channel block. Modifications in
ing these drugs for atrial fibrillation (the major- these chemical structures led to compounds
ity in contemporary practice), the reaction is with more potent sodium channel blocking
quite uncommon when the underlying rhythm is capability. Indeed agents with this property
actually atrial fibrillation but tends to occur (flecainide, propafenone) are very eVective in
shortly after conversion to sinus rhythm; ibuti- suppressing isolated ectopic beats and are
lide may be an exception.4 The clinical parallels among the drugs of choice for treatment of
between torsades de pointes in drug associated re-entrant supraventricular tachycardia in pa-
cases and in the congenital long QT syndromes tients with no underlying structural heart dis-
has suggested the possibility that some patients ease. However, extensive clinical studies with
displaying apparently idiopathic responses to these agents, and drugs that are no longer
drugs may in fact harbour subclinical congenital available but that exerted very similar pharma-
long QT syndrome mutations. With the identifi- cologic properties, have identified a number of
cation of the disease genes in the congenital serious liabilities of sodium channel block.
form of the syndrome has come the possibility of First, in patients with a history of sustained
testing this idea, an area of very active research.5 ventricular tachycardia related to a remote
Most drugs that cause torsades de pointes myocardial infarction, exacerbation of ven-
have as a major pharmacologic action block of tricular tachycardia is common. Such exacer-
a specific repolarising potassium current, IKr. bation presents as a pronounced increase in
Thus, patients are thought to develop drug frequency of episodes, which are often slower
induced torsades de pointes either because the than pre-drug, but less organised and more
channels underlying IKr are unusually sensitive diYcult to cardiovert. Treatment of this
to drug block (which is now recognised with arrhythmia by additional sodium channel block
hypokalaemia and with some mutations) or is undesirable; blockers or sodium infusion
because they harbour subclinical mutations in have been found eVective in anecdotes. Deaths
other repolarising channels. In the latter case, have been reported. The mechanism of ven-
baseline QT intervals can be normal because of tricular tacchyarrhythmia (VT) in these cases is
a robust IKr, but block of the current produces thought to relate to slow conduction in border
exaggerated QT prolongation. zone tissue, and the conduction slowing caused
The management of torsades de pointes by sodium channel blockers tends to further
includes recognition, withdrawal of any oVend- exacerbate the clinical arrhythmia.
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Second, the rate of atrial flutter, a macro- II, moricizine was found to increase mortality
reentrant arrhythmia occurring in the right notably in the two weeks following the institu-
atrium, is usually slowed by sodium channel tion of treatment, although the eVect long term
block. When this occurs, the patient who was less striking than with flecainide and encai-
pre-drug had atrial flutter at 300/min and 2:1 nide. A meta-analysis10 and a non-randomised
atrioventricular (AV) transmission with narrow post-hoc analysis11 suggested that quinidine or
complexes at 150/min may present with wide procainamide treatment in patients with atrial
342 complex tachycardia at 200/min, representing a fibrillation was associated with a higher mor-
slowing of atrial flutter to 200/minute and 1:1 tality than among patients not receiving these
AV transmission. QRS widening often accom- agents. The role of antiarrhythmic drugs to
panies this fast rate since sodium channel block maintain sinus rhythm versus AV nodal blocking
is enhanced at fast rates.6 The management of drugs or other treatment to control rate in atrial
this entity requires recognition, withdrawal of fibrillation is being studied in AFFIRM, whose
oVending agents, and AV nodal blocking drugs. results should be available in the next 23 years.
This reaction can occur not only in patients One consequence of CAST was a general
being treated with flecainide, propafenone, or consensus, on the part of clinical investigators
quinidine for atrial flutter (where, as described and regulatory authorities, that licensing new
above, sodium channel blockers may not be antiarrhythmic drugs might well require demon-
especially eVective) but also in patients whose stration that those drugs did not increase
presenting arrhythmia is atrial fibrillation and mortality. Two large mortality trials have been
is converted by drug to atrial flutter. Many conducted with pure IKr blocking compounds:
experts would not prescribe these drugs to SWORD tested the dextro-rotary (non- block-
patients with atrial fibrillation or flutter without ing) isomer of sotalol, and DIAMOND tested
co-administering an AV nodal blocking drug. dofetilide. In SWORD, d-sotalol increased
Third, sodium channel block increases mortality,12 whereas in DIAMOND, dofetilide
threshold for pacing and defibrillation. produced no eVect on mortality.13 These diVer-
Fourth, the use of the sodium channel ences likely arose from diVerences in trial design,
blockers flecainide or encainide to suppress and in particular eVorts to minimise the
ventricular extrasystoles in patients convalesc- possibility of torsades de pointes during long
ing from myocardial infarction was found in term treatment in DIAMOND. Amiodarone has
the cardiac arrhythmia suppression trial been tested in a CAST-like population and been
(CAST) to increase mortality.7 While the found to exert a modest eVect to decrease
mechanism underlying this eVect is not known, mortality,14 an eVect that may be potentiated by
a synergistic action of sodium channel block co-administration of blockers.15 Despite nu-
and recurrent transient myocardial ischemia to merous attempts, calcium channel blockers have
provoke ventricular tachycardia or ventricular not been shown to exert a major eVect to reduce
fibrillation is strongly suspected from clinical mortality following myocardial infarction.
and animal model studies. The clinical implica- ALIVE is testing a new potassium channel
tion of CAST for contemporary antiarrhyth- blocking agent (azimilide). At this point, the
mic treatment and antiarrhythmic drug devel- mainstay of drug treatment to reduce mortality
opment cannot be underestimated. As a result following myocardial infarction remains thera-
of this landmark trial: pies directed at maintaining a normal cardiovas-
x non-sustained ventricular arrhythmias are cular substrate, such as blockers, angiotensin
generally not treated (or treated with converting enzyme (ACE) inhibitors, HMG-
antiadrenergic agents); CoA reductase inhibitors (statins), and aspirin.
x we recognise increasingly that the risk of
adverse reactions to antiarrhythmic drugs is
driven by an interaction between the drug
and an abnormal electrophysiologic substrate; Drug interactions
x drug development moved away from drugs
with prominent sodium channel blocking Because antiarrhythmic drugs often have nar-
properties to drugs with more prominent
row margins between the doses or plasma con-
eVects to prolong action potentials8;
centrations required to achieve a desired thera-
x and non-pharmacologic therapy has emerged
as a major mode of treatment.9 peutic eVect and those associated with toxicity,
x Most importantly, CAST demonstrated the drug interactions tend to be especially promi-
power of the controlled clinical trial to nent. This diYculty is exacerbated by the fact
evaluate treatments for any disease and the that most patients receiving antiarrhythmic
dangers of relying on surrogate end points drugs receive other treatments as well. Concep-
(such as extrasystoles) to guide drug therapy. tually, drug interactions arise from two distinct
mechanisms, pharmacokinetic and pharmaco-
dynamic. Pharmacokinetic drug interactions
arise when one drug modifies the absorption,
Effect of drugs on long term
distribution, metabolism, or elimination of a
arrhythmia mortality
second. Pharmacodynamic interactions arise
because of interactions that blunt or exaggerate
A number of other studies have also supported a pharmacologic eVects without altering plasma
detrimental eVect of sodium channel blockers in drug concentrations.
the post-myocardial infarction population. Early The greatest likelihood of important phar-
trials with disopyramide and mexiletine both macokinetic drug interactions arises when a
showed trends to increased mortality. In CAST- drug is eliminated by a single pathway and a
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Education in Heart
second drug is administered that modifies the withdrawal or limitations of the drugs use.
activity of that pathway. Identification of CYP3A4 metabolism is induced by co-
specific genes whose expression results in the administration of drugs such as rifampin,
enzymes or transport systems mediating drug phenytoin, and phenobarbital. In this circum-
disposition has led to the realisation that, in stance, concentrations of CYP3A4 substrates
some patients, mutations in these genes can may fall, with attendant loss of pharmacologic
result in abnormal drug disposition even in the eVect. This has been well documented with
absence of interacting drugs. Thus, the field of quinidine and mexiletine.
drug interactions and of genetically deter-
mined drug disposition are closely linked. The CYP2D6
clinical consequences of modulating a drug This enzyme is expressed in the liver and is
disposition pathway depend on the pharmaco- responsible for biotransformation of many
logic eVects produced by altered parent drug blockers (timolol, metoprolol, propranolol),
concentrations and/or altered concentrations propafenone, and codeine. CYP2D6 poor
of active metabolites whose generation de- metabolisers are deficient in CPY2D6 activity,
pends on the pathway targeted. These general on a genetic basis; 7% of whites and African
principles are best understood by considering Americans (but very few Asians) are poor
specific examples (table 4). metabolisers. Quinidine and a number of anti-
depressants (both tricyclics and selective sero-
CYP3A4 tonin reuptake inhibitors such as fluoxetine) are
More drugs are metabolised by this enzyme potent CYP2D6 inhibitors. When these inhibi-
than by any other. CYP3A4 is expressed not tors are given to patients receiving blockers or
only in the liver, but also in the intestine and propafenone (which has weak blocking activ-
other sites, such as kidney. Presystemic drug ity), or such substrate drugs are administered to
metabolism by CYP3A4 in the intestine and patients who are poor metabolisers, exaggerated
the liver is one common mechanism whereby blockade occurs. Indeed, clinical data strongly
some drugs have a very limited systemic avail- support the idea that absence of CYP2D6 activ-
ability. The activity of CYP3A4 varies widely ity increases the likelihood of side eVects during
among individuals, although there is no geneti- propafenone treatment.17 On the other hand,
cally determined polymorphism yet described. absence of CYP2D6 activity in a patient receiv-
As shown in table 4, many widely used cardio- ing codeine results in failure of biotransforma-
active agents are substrates for CYP3A4 and tion to a more active metabolite (morphine).
inhibition or induction of CYP3A4 activity can Thus, in this situation, inhibition of drug
lead to important drug interactions. metabolism actually leads to a (paradoxical)
Perhaps the most spectacular example of a decrease in pharmacologic eVect.
CYP3A4 mediated drug interaction was that
between terfenadine and the CYP3A4 inhibi- P-glycoprotein
tors erythromycin or ketaconazole.16 Terfena- Movement of drugs across cell membranes is
dine is a very potent IKr blocker in vitro but is increasingly recognised as a process dependent
ordinarily almost completely (> 98%) metabo- on normal expression and function of specific
lised by CYP3A4 before entry into the systemic transport molecules. The most widely stud-
circulation. With co-administration of ied of these is P-glycoprotein, expressed on the
CYP3A4 inhibitors, this presystemic metabo- luminal aspect of enterocytes, on the biliary
lism is inhibited, terfenadine plasma concen- canalicular aspect of hepatocytes, and the cap-
trations rise > 100 fold, and torsades de illaries of the bloodbrain barrier. Many widely
pointes can ensue. A similar mechanism also used drugs are P-glycoprotein substrates, al-
explains torsades de pointes during treatment though the functional consequences of
with astemizole and cisapride, and has led to P-glycoprotein inhibition are small because
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Arrhythmias
Torsades de pointes Acute: QT prolonging drugs:
Magnesium Quinidine
Isoproterenol Procainamide
Pacing Disopyramide
344 Raise serum K+ Sotalol
Chronic QT prolongation: Ibutilide
Blockers Dofetilide
Pacing ???Amiodarone
Polymorphic VT with short QT intervals Anti-ischaemic intervention Lidocaine, procainamide (ineVective)
Intravenous amiodarone
Sustained monomorphic VT IV procainamide or sotalol Lidocaine (ineVective)
RV outflow tract VT, fascicular VT Verapamil
Blocker
Adenosine (acutely)
QT interval prolongation Flecainide Quinidine
Propafenone Orocainamide
Lidocaine Disopyramide
Mexiletine Sotalol
???Amiodarone Ibutilide
Dofetilide
???Amiodarone
Atrial fibrillation + structural heart disease Flecainide
Atrial fibrillation with rapid ventricular rate and pre-excitation IV procainamide cardioversion Verapamil
Adenosine
Digitalis
Other concomitant conditions
Heart failure Digitalis Diltiazem, verapamil
Also acceptable: Blockers if severe
Amiodarone Flecainide
Dofetilide Disopyramide
Quinidine
Sinus/AV nodal disease All drugs discussed have the potential to worsen
bradyarrhythmias, particularly:
Diltiazem, verapamil
Blockers
Digitalis
Amiodarone
DiVuse conduction system disease Above + most other antiarrhythmics
Chronic lung disease Amiodarone
Inflammatory arthritis Procainamide
Chronic bowel disease Quinidine (exacerbates diarrhoea)
Verapamil, disopyramide (exacerbate constipation)
Asthma Blockers
Propafenone
Tremor Lidocaine
Mexiletine
This table is not meant to supplant discussions of treatments of choice for various arrhythmia syndromes outlined in other parts of this series. Rather, specific clinical
conditions which may dictate an unusual or specific choice of drugs are presented.
IV, intravenous.
most drugs have other pathways for their channel blockers are co-administered, pro-
elimination. Clinically, the most important nounced bradycardia or heart block occurs
P-glycoprotein substrate in cardiovascular use is primarily in patients with underlying conduc-
digoxin, which does not undergo extensive tion system disturbances. Similarly, exacerba-
metabolism by enzymes such as CYP3A4 or tion of heart failure is more of a problem when
CYP2D6. Rather, its bioavailability is limited by multiple drugs with cardiodepressant actions
re-excretion by P-glycoprotein into the intestinal (including, prominently, antiarrhythmics) are
lumen, and its elimination is accomplished by co-administered to patients with underlying
excretion by P-glycoprotein and possibly other heart disease.
transporters in liver and kidney. The eVect of
multiple, structurally unrelated drugs such as
quinidine, verapamil, amiodarone, cyclosporine,
erythromycin, and itraconazole to increase Putting it all together: matching the
digoxin concentrations likely has the common patient, the drug, and the arrhythmia
mechanism of P-glycoprotein inhibition.18
Decades of clinical investigation and, more
recently, whole animal, cellular, molecular, and
Pharmacodynamic drug interactions
genetic studies, have now positioned clinicians
to more rationally prescribe and monitor treat-
Pharmacodynamic interactions tend to mani- ment with drugs designed to treat cardiac
fest primarily in patients with underlying heart arrhythmias. A number of very important prin-
disease. Thus, when blockers and calcium ciples can be enunciated based on these data.
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5. Roden DM, Lazzara R, Rosen MR, et al, the SADS 13. Torp-Pedersen C, Moller M, Bloch-Thomsen PE, et al.
Foundation Task Force on LQTS. Multiple mechanisms in Dofetilide in patients with congestive heart failure and left
the long QT syndrome: current knowledge, gaps, and future ventricular dysfunction. Danish investigations of arrhythmia
directions. Circulation 1996;94:19962012. and mortality on dofetilide study group. N Engl J Med
6. Crijns HJ, van Gelder IS, Lie KI. Supraventricular 1999;341:85765.
tachycardia mimicking ventricular tachycardia during 14. Connolly SJ, Cairns J, Gent M, et al. Effect of
flecainide treatment. Am J Cardiol 1988;62:13036. prophylactic amiodarone on mortality after acute myocardial
7. CAST Investigators. Preliminary report: effect of infarction and in congestive heart failuremeta-analysis of
encainide and flecainide on mortality in a randomized trial of individual data from 6500 patients in randomised trials.
Lancet 1997;350:141724.
346 arrhythmia suppression after myocardial infarction. N Engl J
Med 1989;321:40612. A meta-analysis of EMIAT, CAMIAT, and other post-MI
The cardiac arrhythmia suppression trial (CAST) was a studies with amiodarone indicating a modest but
landmark study that defined the phenomenon of increased demonstrable effect of the drug to reduce mortality.
mortality during long term antiarrhythmic drug treatment. 15. Boutitie F, Boissel JP, Connolly SJ et al. Amiodarone
CAST has had huge implications for use of available interaction with beta-blockers : analysis of the merged
drugs, development of new drugs, and the use of the large EMIAT (European myocardial infarct amiodarone trial) and
randomised placebo controlled trial to evaluate hard end CAMIAT (Canadian amiodarone myocardial infarction trial)
points (such as mortality) during drug treatment, rather databases. Circulation 1999;99:226875.
than relying on drug effects on surrogates such as
extrasystole suppression. 16. Woosley RL, Chen Y, Freiman JP, et al. Mechanism of
the cardiotoxic actions of terfenadine. JAMA
8. Hondeghem LM, Snyders DJ. Class III antiarrhythmic 1993;269:15326.
agents have a lot of potential, but a long way to go: reduced Terfenadine was found to be a potent IKr blocker and
effectiveness and dangers of reverse use-dependence. elevated plasma terfenadine concentrations resulting from
Circulation 1990;81:68690. inhibition of the drugs CYP3A4-mediated metabolism were
9. Buxton AE, Lee KL, Fisher JD, et al. A randomized thereby mechanistically linked to torsades de pointes.
study of the prevention of sudden death in patients with
coronary artery disease. Multicenter unsustained tachycardia 17. Lee JT, Kroemer HK, Silberstein DJ, et al. The role of
trial investigators. N Engl J Med 1999;341:188290. genetically determined polymorphic drug metabolism in the
beta-blockade produced by propafenone. N Engl J Med
10. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and 1990;322:17648.
safety of quinidine therapy for maintenance of sinus rhythm This study demonstrated that a pharmacological response
after cardioversion. Circulation 1990;82:110616. during drug treatment ( blockade with propafenone) is
This meta-analysis indicated that while quinidine appears tightly linked to CYP 2D6 phenotype, with poor metaboliser
more effective than placebo in maintaining sinus rhythm, it subjects developing higher concentrations, and greater
is associated with a > 3 fold increase in mortality. While blockade.
the study has been criticised because many of the original
reports were published before concentration monitoring or 18. Fromm MF, Kim RB, Stein CM, et al. Inhibition of
awareness of the digoxinquinidine interaction, and P-glycoprotein-mediated drug transport: a unifying
because some of the excess quinidine deaths were mechanism to explain the interaction between digoxin and
non-cardiac (malignancy, suicide), it nevertheless quinidine. Circulation 1999;99:5527.
highlighted the problem further examined prospectively, This study used combined experiments in in vitro models
with variable outcomes, in studies such as CAST, CAST-II, and in genetically modified mice to implicate quinidine
IMPACT, EMIAT, CAMIAT, SWORD, and DIAMOND. inhibition of digoxin transport by P-glycoprotein as a major
mechanism underlying the effect of quinidine to elevate
11. Flaker GC, Blackshear JL, McBride R, et al. serum digoxin, recognised 20 years previously.
Antiarrhythmic drug therapy and cardiac mortality in atrial
fibrillation. J Am Coll Cardiol 1992;20:52732. 19. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention
A retrospective analysis of antiarrhythmic drug treatment in of symptomatic recurrences of paroxysmal atrial fibrillation in
1330 patients enrolled in the SPAF study indicated > 2.5 patients initially tolerating antiarrhythmic therapy: a
multicenter, double-blind, crossover study of flecainide and
website
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Additional references
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d-sotalol on mortality in patients with left ventricular Amiodarone for resuscitation after out-of-hospital cardiac appear on the
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Lancet 1996;348:712. 1999;341:8718.
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Notes