European Heart Journal (1999) 20, 51–57

Article No. euhj.1998.1354, available online at http://www.idealibrary.com on

Cardioprotection by opening of the KATP channel in

unstable angina
Is this a clinical manifestation of myocardial preconditioning?
Results of a randomized study with nicorandil
D. J. Patel, H. J. Purcell and K. M. Fox on behalf of the CESAR 2 investigation
Royal Brompton and Harefield NHS Trust, London, U.K.

Aims To assess the anti-ischaemic and anti-arrhythmic on placebo (P=0·087 patients; P<0·0001 runs). Three
effects and overall safety of nicorandil, an ATP sensitive nicorandil patients had four runs of supraventricular tachy-
potassium (K + ) channel opener, with ‘cardioprotective’ cardia, compared to 15 runs in nine patients on placebo
effects, in patients with unstable angina. (P=0·14 patients; P=0·017 runs). Eleven (12·4%) patients
on nicorandil had 37 episodes of transient myocardial
Methods In a multicentre, randomized, double-blind, ischaemia (mostly silent) compared with 74 episodes in 21
parallel-group, placebo-controlled study, oral nicorandil (21·2%) patients on placebo (P=0·12 patients; P=0·0028
20 mg twice daily or a matching placebo was administered episodes). In the overall safety analysis, which included all
for a minimum of 48 h to patients admitted with unstable patients who received at least one dose of study medication,
angina. Treatment was standardized to include, where there were no significant differences in the rates of myo-
tolerated, oral aspirin, a beta-blocker and diltiazem. Con- cardial infarction or death between the nicorandil or
tinuous Holter ECG monitoring was performed for 48 h to placebo-treated groups.
assess the frequency and duration of transient myocardial
ischaemia and any tachyarrhythmia, as the predefined Conclusions Nicorandil, added to aggressive anti-anginal
end-points of the study. A pain chart recorded the inci- treatment for unstable angina, reduces transient myocardial
dence and severity of chest pain throughout the study ischaemia, non-sustained ventricular, and supraventricular
period. Patients with myocardial infarction identified arrhythmia compared to placebo. The anti-arrhythmic
retrospectively from troponin-T analysis were excluded. activity with nicorandil is probably a secondary effect
resulting from its anti-ischaemic action and we suggest
Results Two hundred and forty-five patients were re- that this may be related to its effect on the ATP
cruited into the study. Forty-three patients were excluded sensitive potassium channel causing pharmacological
with an index diagnosis of myocardial infarction, two were preconditioning.
not randomized and 12 had unsatisfactory tape data. In the (Eur Heart J 1999; 20: 51–57)
remaining 188 patients, six out of 89 patients (6·7%) on
nicorandil experienced an arrhythmia, compared with 17 Key Words: Unstable angine, nicorandil, ischaemic pre-
out of 99 patients (17·2%) on placebo (P=0·04). Three conditioning.
nicorandil patients experienced three runs of non-sustained
ventricular tachycardia compared to 31 runs in 10 patients See page 2 for the Editorial comment on this article

Introduction half of all acute cardiac admissions[1]. A combination of

anti-ischaemic and anti-thrombotic therapy is routinely
Unstable angina represents part of a spectrum of acute used in order to control symptoms and also to prevent
ischaemic syndromes which now account for more than progression to myocardial infarction and death. The risk
of an adverse outcome is greatest soon after the onset of
Revision submitted 9 October 1998, and accepted 14 October 1998. symptoms and declines rapidly approaching the same
Correspondence: Dr K. M. Fox, Consultant Cardiologist, level to that of patients with stable coronary disease
Royal Brompton & Harefield NHS Trust, Sydney Street, within 6 months[2]. Despite conventional medical
London SW3 6NP, U.K. therapy, the outcome continues to remain poor with

0195-668X/99/010051+07 $18.00/0  1999 The European Society of Cardiology

52 D. J. Patel et al.

10–15% of patients progressing to myocardial infarction thrombolysis, or angina within 1 month of infarction
or death[2,3], with the worst outcome in patients whose were excluded. Patients were also excluded for the
symptoms fail to settle with conventional medical following reasons: uninterpretable ECG, e.g. left bundle
therapy[4]. branch block, left ventricular hypertrophy and strain, or
Nicorandil, a nicotinamide ester, is the first digoxin effect; severe hypotension, known contraindi-
clinically available adenosine triphospate (ATP) sensi- cation to nicorandil; secondary angina; coronary angi-
tive potassium (K + ) channel opener. Structurally it is a oplasty or bypass surgery in the preceding 3 months;
combination of a nitrate-like moiety and a nicotinamide known arrhythmia; valvular heart disease; women of
derivative with K + channel opening properties. Like child bearing potential. ECG changes were not specified
nitrates, nicorandil reduces preload and afterload while for inclusion.
also increasing coronary blood flow[5]. By opening the All patients had an initial resting ECG,
KATP sensitive channel, nicorandil causes hyperpolariz- underwent 48 h of continuous ST segment and arrhyth-
ation, and a shortening of the action potential duration mia monitoring (Reynolds Medical Tracker TR1), and
which is potentially pro-arrhythmic. It also causes a kept a pain chart. Blood samples for cardiac enzymes,
secondary reduction in calcium influx, leading to including a troponin T level (Boehringer Mannheim
relaxation of arterial smooth muscle and dilatation of U.K.), were taken at 12, 24 and 48 h. Patients with a
peripheral and small coronary resistance arterioles[6]. retrospective diagnosis of myocardial infarction at the
Nicorandil may also afford additional myocardial time of entry defined as: (a) acute persistent ST elevation
protection through ischaemic preconditioning[7]. Pre- of >0·1 mV with new Q wave evolvement (equivalent
conditioning is the phenomenon in which short bursts of posterior infarction changes); (b) severe chest pain
ischaemia with intermittent reperfusion can protect the >60 min duration; (c) raised cardiac enzymes (including
myocardium from a subsequent lethal ischaemic insult. troponin T) were withdrawn from the study as defined a
It is proposed that the mechanism associated with this priori in the protocol.
protection occurs as a consequence of opening this Drug treatment was standardized to include:
ATP-sensitive channel. Hence nicorandil may, in part, diltiazem 180–360 mg daily, atenolol 50–100 mg daily
have as its mode of action an ability to mimic this or metoprolol 12·5–50 mg three times a day where
preconditioning phenomenon. This may be important in tolerated, or not contraindicated; aspirin 150 mg daily.
two respects; any myocardial damage that may occur Intravenous heparin and nitrates were prescribed at
would be expected to be less and also the cell should be the physician’s discretion. Patients were randomized to
able to withstand the effects of prolonged ischaemia for receive either nicorandil 20 mg orally twice daily or
longer. It may then be possible to institute effective matching placebo for 48 h, although study medi-
treatment aimed at restoring coronary blood flow in cation could be administered for up to 28 days if
timely fashion. appropriate.
Nicorandil has been shown to have a comparable The predefined end-points of the study were
anti-anginal effect to nitrates, beta-blockers and calcium the frequency of tachyarrhythmias and myocardial
antagonists in double-blind randomized studies[8,9]. ischaemic episodes. Holter tapes were analysed on a
However, the action of nicorandil, as a pharmacological Pathfinder 3 Mark II analyser (Reynolds Medical Ltd).
preconditioning agent, has not been extensively tested in The incidence, duration and association of chest pain
clinical circumstances. was recorded for all ischaemic episodes. All arrhythmic
This study was designed to test the overall safety activity was recorded including the number of ectopics
and efficacy of nicorandil, looking at putative cardiopro- and couplets. For the purposes of analysis, episodes of
tective properties and any likelihood of pro-arrhythmia. ventricular tachycardia, and supraventricular tachy-
Nicorandil was administered to patients with unstable cardia were defined a priori as runs of a minimum of
angina, on a full anti-anginal regimen that would leave three consecutive beats of d100 beats . min
1. Other
little possibility for the drug to have any additional arrhythmias were also documented.
haemodynamic effects. Randomization was by sealed envelopes and
both the study investigator and the Holter analyser were
unaware of the drug treatment allocation. Ischaemia
was defined as the occurrence of _0·1 mV planar or
Methods downsloping ST segment depression from baseline at
80 ms after the J point lasting for more than 60 s. ST
This was a multicentre study conducted at 14 centres in elevation was defined as the development of _0·2 mV
the United Kingdom and Ireland. The full list of inves- from the J point. Each episode had to be separated by a
tigators can be found in Appendix 1. Patients admitted return of the ST segment to baseline for at least 1 min to
acutely with unstable angina between the age of 30–80 be counted as a discrete episode. Changes in the T wave
years were included. Unstable angina was defined as the vector in the absence of ST segment changes were not
new onset of angina (c1 month); acceleration of pre- recorded or included in the analysis.
viously stable angina; or angina occurring at rest or Written informed consent was obtained from
at night. Patients with acute Q, non-Q wave myo- all patients recruited into the study. The study was
cardial infarction, aborted myocardial infarction with approved by the ethics committee of the Royal

Eur Heart J, Vol. 20, issue 1, January 1999

 Cardioprotection by opening the KATP channel in UA 53

Total patients enrolled

243

Patients excluded;
MI 43
Poor Holter 12

Intention-to-treat population
with satisfactory data
188

Placebo Nicorandil

Total patients Total patients

99 89

Patients with no ischaemia Patients with no ischaemia

78 (78·9%) 78 (87·6%)
Patients with no VT Patients with no VT
77 (77·8%) 79 (88·8%)

Patients with ischaemia Patients with ischaemia

21 (21·1%) 11 (12·4%)
Patients with VT Patients with VT
22 (22·2%) 10 (11·2%)

Figure 1 Recruitment and patient allocation, including outcome.

Brompton Hospital, and also of each individual episodes were also compared between the treatment
participating hospital. groups. The total duration of ischaemia was compared
using the Wilcoxon 2-sample test and the number of
patients with total ischaemia of >60 min was compared
Data analysis using Fisher’s exact test. The frequency of severe chest
pain, d4 (scale 1–5), was also compared using Fisher’s
An intention-to-treat analysis was conducted for all exact test.
patients with unstable angina who did not, in retrospect,
have an index diagnosis of acute myocardial infarction,
and had satisfactory Holter data. This was prespecified Results
in the protocol.
The frequency (episodes), and incidence (patients The recruitment and patient allocation including the
with such episodes), of transient myocardial ischaemia primary outcome is shown in Fig. 1.
and arrhythmias (ventricular, supraventricular tachy- In total, 245 patients were recruited, 243 of
cardia, ventricular ectopic beats) was analysed between whom (121 nicorandil; 122 placebo) received at least one
the two treatment groups. The incidences were com- dose of study medication. Forty-three patients were
pared using Fisher’s exact test, and the frequency of excluded having sustained myocardial infarction at
episodes using a log-linear model. Frequency of ven- admission; the remaining 200 patients were eligible for
tricular premature beats was tested using the Wilcoxon the intention-to-treat analysis. In a further 12 patients,
2-sample test. The differences for symptomatic and silent the Holter data was unsatisfactory, thus 188 patients

Eur Heart J, Vol. 20, issue 1, January 1999

54 D. J. Patel et al.

Table 1 Patient demographic details

Nicorandil Placebo
Demographic characteristics
n=96 n=104

Males 67 70
Age mean (SD) 58·59·6 61·311·2
Hypertension 36 42
Diabetes 12 11
Hyperlipidaemia 25 15
Family history of CAD 61 66
Previous MI 41 49
CABG/PTCA 23 25
Known CAD on angiography 32 34
Stable angina 64 70
Baseline STT wave changes 56 65
Normal baseline ECG 32 31
Mean time from last chest pain (h) 13·8 13·9
Mean duration of last chest pain (min) 36·9 32·5

CAD=coronary artery disease; MI=myocardial infarction.

100
90
% Patients on drug

80
70
60
50
40
30
20
10
0
in g ke
r rin iv po
pir nta loc pa ate ate
As A -b He tr tr
Ca eta Ni Ni
B
Figure 2 Percentage of patients receiving types of anti-anginal
and anti-thrombotic medication during the study period. (Ca
Antag=calcium antagonist; iv=intravenous, po=oral). =nicoran-
dil; =placebo.

comprised the cohort for arrhythmia and transient episodes of transient ischaemia, 85 (77%) of which were
myocardial ischaemia analysis. The demographic details silent. Figure 3 shows that significantly fewer episodes
of the study population are shown in Table 1. There of silent or painful ischaemia occurred in 11 (12·4%)
were no significant differences in the baseline character- patients on nicorandil compared to 21 (21%) on placebo.
istics of patients on nicorandil or placebo. Two thirds of
the patients were male; 79% had a documented history
of coronary artery disease; in 68% the resting ECG was 80
abnormal, and the remainder had either a documented
Number of episodes of TMI

70
history of coronary artery disease or an abnormal ECG.
60
There were similar proportions of patients re-
P = 0·0028
ceiving triple and quadruple anti-anginal therapy in each 50
group prior to enrolment. The anti-anginal therapy 40
during the study period was similar for the nicorandil
and placebo groups, see Fig. 2. Although nitrate use was 30
discretionary and relatively common, it was balanced 20
between the treatment groups. 10
0
Myocardial ischaemia Nicorandil Placebo
Figure 3 Numbers of episodes of transient myocardial
Transient myocardial ischaemia ischaemia (TMI) showing significantly fewer silent ( )
During a mean of 41 h per patient of continuous and painful ( ) episodes in the nicorandil vs the placebo-
ST segment monitoring, 33 (17·6%) patients had 111 treatment groups.

Eur Heart J, Vol. 20, issue 1, January 1999

 Cardioprotection by opening the KATP channel in UA 55

35 on placebo having at least one couplet compared to 11

P < 0·001
(12·4%) in the nicorandil group (P=0·03).
30
Number of episodes

25
20
P = 0·017 Clinical outcome
15
During active treatment in the intention-to-treat cohort
10 (n=200) there were no deaths and two non-fatal myo-
5 cardial infarctions in the placebo group, and no events
0
in the nicorandil treated group.
VT SVT Two hundred and forty-three patients in the
safety analysis received at least one dose of study
Figure 4 Numbers of episodes of ventricular tachycardia
medication. The analysis therefore contains those
(VT) and supraventricular tachycardia (SVT) showing
significantly fewer episodes of these arrhythmias in the patients excluded because of pre-admission myocardial
nicorandil ( ) vs the placebo ( ) treated groups. infarction but who were initially randomized. Of the
cardiovascular-related serious side-effects, seven myo-
cardial infarctions occurred during the study period
Patients on nicorandil were less likely to have ischaemia, (four in the nicorandil group and three in the placebo
and fewer patients had d60 min of ischaemia, in com- group). Six of these (four nicorandil, two placebo) were
parison with those on placebo, although this trend did diagnosed within 12 h of enrolment. One myocardial
not reach statistical significance. The range of transient infarction (placebo) occurred between 12–48 h after
ischaemic episodes in each group was similar, and enrolment. Two myocardial infarctions (nicorandil)
without individual patient ‘outliers’ who might skew the occurred after the study period. Two patients receiving
results. nicorandil were considered to have a causal relationship
between study drug and event by the investigator (one
Chest pain related to hypotension and the other chest pain). There
Chest pain during the study was reported as an adverse were six deaths (four nicorandil and two placebo). None
event by 20 (16·5%) patients on nicorandil and 38 of these was considered by the investigators to be related
(31·1%) on placebo (P=0·008). Severe chest pain (d4 on to treatment.
the pain chart) was recorded by 11 out of 96 (11·5%)
patients on nicorandil compared to 14 out of 104
(13·5%) on placebo (P ns).
Discussion
Our results have shown that oral nicorandil adminis-
Arrhythmias tered in addition to standard maximal anti-anginal
therapy to patients with unstable angina offers signifi-
Ten (11·2%) patients in the nicorandil group and 22 cant additional benefit by reducing transient myocardial
(22·8%) on placebo had some form of arrhythmia during ischaemia and tachyarrhythmias. There was no increase
Holter monitoring (P=0·05). There were no sustained in the incidence of hypotensive adverse effects in patients
episodes of tachyarrhythmias. In total, 13 patients receiving nicorandil, i.e. 7 (6·0%) vs placebo 5 (4·0%)
experienced 34 episodes of ventricular tachycardia. The and therefore it is unlikely that oral nicorandil had
number of episodes of ventricular tachycardia was sub- any significant haemodynamic effects in these patients
stantially lower in patients on nicorandil compared to who were already on treatment with beta-blockade in
placebo (Fig. 4). There was also a strong trend for combination with diltiazem, and in the majority of cases
fewer patients with ventricular tachycardia to receive on either oral or intravenous nitrates; however, this was
nicorandil compared to placebo. not assessed formally in the study. We propose that the
Supraventricular tachycardia occurred on 19 beneficial effects of nicorandil are due to pharmaco-
occasions in 12 patients. The number of episodes of logical preconditioning resulting in a significant
supraventricular tachycardia was significantly lower on reduction in the number of ischaemic events.
nicorandil compared to placebo and there was a trend Unstable angina is associated with an increased
showing that fewer patients experienced supraventricu- risk of progression to death, or myocardial infarction.
lar tachycardia whilst on nicorandil. Atrial fibrillation Aspirin is effective in reducing myocardial infarction
was relatively uncommon, with three episodes in two and death, and heparin has additive benefit in high risk
patients receiving nicorandil and three episodes in three groups. Symptom control is usually achieved with intra-
patients on placebo. venous nitrates and oral beta-blocker therapy often in
Ventricular premature complexes (couplets combination with a calcium antagonist. The effect of
and/or aberrant beats) were noted in 68 (76·4%) patients anti-anginal treatment on outcome has, in general, been
on nicorandil and in 82 (82·8%) on placebo. Couplets considered to be small. Despite a combination regimen,
were more frequent on placebo, with 23 (23·2%) patients a significant proportion of patients do not improve and

Eur Heart J, Vol. 20, issue 1, January 1999

56 D. J. Patel et al.

these represent the group at greatest risk of an adverse drug appears to have a cardioprotective effect evidenced
outcome. In this study, almost all patients received oral by less ischaemia and this is consistent with a
aspirin, a calcium antagonist and beta-blockers at base- preconditioning-like action[15].
line. The latter were tolerated by the majority such that These findings suggest that nicorandil has anti-
over 70% of the patients received all three drugs. Base- ischaemic effects for patients with unstable angina with
line nitrate therapy was not mandated in the protocol; synergistic action to a currently accepted anti-anginal
however, over 50% of the patients received additional iv drug treatment regimen which is possibly related to its
or oral nitrates. Transient myocardial ischaemia, the cardioprotective action. Its effect in reducing arrhythmic
majority of which was silent, was evident in 16% of activity is a novel finding, suggesting a potential role
the patients, and nicorandil significantly reduced the in preventing sudden arrhythmic cardiac death in the
number of both painful and silent episodes of ischaemia. setting of acute coronary syndromes.
The number of patients with ischaemia, or severe ischae- There was no significant difference in the rates of
mia, showed a trend in favour of nicorandil, although death or myocardial infarction between the nicorandil or
not significantly so. Recurrent chest pain was less placebo groups in the overall safety analysis. However,
frequent in patients on nicorandil, although similar further large scale studies are now warranted to assess its
numbers of patients experienced severe pain. effects on prognosis and adverse outcome in acute
In stable coronary disease, nicorandil has been coronary syndromes; or whether this action may ‘buy
shown to be effective to a similar degree to beta-blockers time’ while other treatments or interventions can
and calcium antagonists[5]. The efficacy of nicorandil in effectively restore coronary blood flow.
unstable angina has been confined to a few relatively
small or non-randomized studies. In a double-blind This study was supported by a research grant from Rhone
Poulenc Rorer Pharmaceuticals Ltd. Troponin T reagents were
study of 74 patients[10] there was a trend for intravenous kindly supplied by Boehringer Mannheim Ltd. We are grateful for
nicorandil to abolish anginal attacks in more patients the invaluable help in conducting the study from the late Dr Ian
(75%) than isosorbide dinitrate (55%). Another small Rumfitt and the technical assistance of Christine Wright and
non-randomized study showed an improvement in Debbie Clarke. We also appreciate help from Professor Derek
Yellon in the interpretation of our results.
otherwise refractory unstable patients with intravenous
nicorandil[11].
There have as yet been no studies evaluating the
efficacy of combining nicorandil with other anti-anginal References
agents. In the present study, nicorandil added to ag-
[1] Neuhaus KL. Coronary thrombosis – defining the goals,
gressive medical therapy was effective. This suggests that improving the outcome. Presentation during XVIIIth
the anti-ischaemic action is probably mediated via its Congress of the European Society of Cardiology, 1996.
effect on ATP sensitive K + channels, and not merely due [2] Braunwald E, Mark DB, Jones RH et al. Unstable Angina:
to its nitrate moiety. These findings lend further support Diagnosis and management. Clinical practice guideline no. 10.
page 16, AHCPR publications no. 94-0602. Rockville MD:
to the findings from animal studies suggesting that the Agency for Health Care Policy and Research and the National
benefits of nicorandil may be independent of its haemo- Heart, Lung and Blood Institute, Public Health Service, U.S.
dynamic or coronary vasodilatory effects. Nicorandil Dept of Health and Human Services 1994.
has been shown to provide cardioprotection in several [3] Anderson HV, Cannon CP, Stone PH et al. One-year results
of the thrombolysis in myocardial infarction (TIMI) IIIB
animal models of reversible or irreversible ischaemia–
clinical trial. J Am Coll Cardiol 1995; 26: 1643–50.
reperfusion, and to reduce myocardial infarct size after [4] Grambow DW, Topol EJ. Effect of maximal medical therapy
periods of sustained ischaemia[12]. In addition, studies on refractoriness of unstable angina pectoris. Am J Cardiol
using human muscle preparations have already linked 1992; 70: 577–81.
the protection observed with the opening of this [5] Purcell H, Patel D, Mulcahy D, Fox KM. Nicorandil. In:
Messerli FH ed. Cardiovascular drug therapy. Philadelphia:
channel[13]. The effect of nicorandil on ventricular and WB Saunders, 1996: 1638–45.
supraventricular arrhythmic activity was prespecified as [6] Akai K, Wang Y, Sato K et al. Vasodilatory effect of
a primary end-point in this protocol. Patients with nicorandil on coronary arterial microvessels: Its dependency
unstable angina are at risk of sudden death, although on vessel size and the involvement of the ATP-sensitive
potassium channels. J Cardiovasc Pharmacol 1995; 26: 541–7.
there is little published documentation of frequent
[7] Yellon DM, Baxter GF, Marber MS. Angina reassessed; pain
tachyarrhythmias in this subset. Nicorandil, by opening or protector? Lancet 1996; 347: 1159–62.
K + ATP sensitive channels, causes hyperpolarization and [8] Krumenacker M, Roland EO. Clinical profile of nicorandil:
reduces the duration of the action potential and the An overview of its haemodynamic properties and therapeutic
effective refractory period, which, in theory, might efficacy. J Cardiovasc Pharmacol 1992; 20: S93–S102.
[9] Frampton J, Buckley M, Fitton A. Nicorandil: a review of its
increase arrhythmogenicity[14], although this has not as pharmacology and therapeutic efficacy in angina pectoris.
yet been demonstrated in clinical usage. Nicorandil may Drugs 1992; 44: 625–55.
afford myocardial protection through opening the [10] Kato K, Iinuma H, Hirosawa K et al. Clinical evaluation of
K + ATP sensitive channel. We believe that the anti- intravenous SG-75 in treatment of unstable angina – a multi-
centre double-blind comparative study with intravenous
arrhythmic action demonstrated in this study is more
ISDN. Rinsho Iyaku 1991; 7: 2031–54.
likely to occur as a consequence of the reduction in [11] Fukami K, Haze K, Sumiyoshi T et al. Beneficial effects of
myocardial ischaemia with this drug, i.e. through its intravenous nicorandil in refractory unstable angina. Eur
preconditioning-like effect. More appropriately, the Heart J 1988; 9: 64.

Eur Heart J, Vol. 20, issue 1, January 1999

 Cardioprotection by opening the KATP channel in UA 57

[12] Klein HH, Pich S, Lindert-Heimberg S, Schade-Brittinger C, Royal Sussex Hospital, Brighton; Dr. I. Findlay, Royal
Maisch B, Nebendahl K. Comparative study on the effects Alexandra Hospital, Paisley, Dr K. Fox, Royal
of intracoronary nicorandil and nitroglycerin in ischaemic,
reperfused porcine hearts. Eur Heart J 1995; 16: 603–9. Brompton Hospital, London; Dr J.S.R. Gibbs, Bromley
[13] Speechly-Dick M, Grover G, Yellon DM. Does ischaemic Hospital, Bromley; Dr T.W. Greenwood, West
preconditioning in the human involve protein kinase C and Middlesex University Hospital, Isleworth; Dr W.G.
the ATP-dependent K + channel? Circ Res 1995; 77: 1030–5. Henry, Wycombe General Hospital, High Wycombe; Dr
[14] Billman GE. Role of the ATP sensitive potassium channel in
W. Hubbard, Royal United Hospital, Bath; Dr M. Joy,
extracellular potassium accumulation and cardiac arrhyth-
mias during myocardial ischaemia. Cardiovasc Res 1994; 28: St Peters Hospital, Chertsey; Dr D. Lindsay, Gloucester-
762–9. shire Royal Hospital, Gloucester; Dr R.G. Murray,
[15] Vegh A, Szekeres L, Parratt JR. Protective effects of precon- Birmingham Heartlands Hospital, Birmingham; Dr D.
ditioning the ischaemic myocardium involve cyclo-oxygenase Mulcahy, Adelaide Hospital, Dublin, Ireland; Dr J
products. Cardiovasc Res 1990; 24: 1020–3.
Murphy, Darlington Memorial Hospital, Dr G Sutton,
The Hillingdon Hospital, Hillingdon; Dr A. Timmis,
London Chest Hospital, London.
Appendix 1
The clinical European studies in angina and revascular-
isation (CESAR) 2 investigators were: Dr C. Davidson,

Eur Heart J, Vol. 20, issue 1, January 1999