EDUCATION IN HEART VOL 3 - PART 2 docx

4 ACUTE MYOCARDIAL INFARCTION:
REPERFUSION TREATMENT
Flavio Ribichini, William Wijns
T
he decision over whether to treat acute myocardial infarction (AMI) with a balloon or infusion
of fibrinolytics remains controversial. During the past few years profound changes in both
treatment modalities
1–3 w1 w2
have substantially changed the arguments surrounding this long-
standing debate.
w3–5
The evidence shows that the alternative use of primary angioplasty or
fibrinolysis is rarely an option, either because angioplasty is simply not available or because the
patient is not eligible for fibrinolysis. This evidence reflects the difference in “applicability” of each
treatment—thatis,theproportionofpatientsinwhomonlyoneofthetreatmentswouldbesuit-
able versus patients in whom either treatment would be appropriate. As a matter of fact, primary
angioplasty is applicable to almost all victims of AMI (82–90% of patients randomised to primary
angioplasty actually undergo the procedure), but it is not available to the majority of patients. Con-
versely, fibrinolysis is a widely available treatment but “applicable” to a variable percentage of
patients which does not reach 50%. The large number of patients with AMI to whom fibrinolysis is
not administered represents a big challenge for the future, and perhaps the most rational and
undisputed argument in favour of the use of primary angioplasty.
The best reperfusion treatment is one that achieves the highest rate of early, complete and sus-
tained infarct related artery patency in the largest number of patients, but with the lowest rate of
undesirable effects. The results obtained with both treatments, in the way they were applied before
the latest breakthroughs in the field, can be represented by a geometrically opposing relation
between “applicability” and “efficacy” (fig 4.1).
c
UNCONTROVERSIAL EVIDENCE IN FAVOUR OF FIBRINOLYTIC TREATMENT
Clinical trials and experience have identified the following landmarks in the reperfusion treatment
of ST segment elevation AMI.

c
The daily administration of 162.5 mg of aspirin orally from the first day of AMI and continued
for 30 days reduces the 30 day vascular mortality rate by 23% without risk of stroke.
w6
c
Intravenous infusion of streptokinase within six hours after AMI onset reduces 30 day total vas-
cular mortality by 25%, but at the cost of 2–3 strokes per 100 patients treated and 3 severe bleed-
ings requir ing transfusion per 1000 patients treated. Combined treatment with aspirin has syn-
ergistic effects and will prevent 52 vascular deaths per 1000 patients treated and reduce
significantly the risk of reinfarction.
w6
c
The initial benefit of streptokinase treatment on mortality is maintained at 10 year follow up.
4
c
The use of recombinant tissue plasminogen activator (r t-PA) using the “accelerated” dosing
schedule plus heparin (instead of streptokinase) prevents another 10 deaths but causes two
more strokes per 1000 patients treated.
5
c
Pre-hospital fibrinolysis can reduce one year mortality
w7
and should be considered when trans-
port time exceeds 60 minutes.
w8
c
The combination of full dose of abciximab and half dose reteplase reduces non-fatal complica-
tions of AMI, but yields similar mortality rate compared with reteplase alone.
6
EVIDENCE IN FAVOUR OF PRIMARY ANGIOPLASTY: CONSENSUS STATEMENTS

All the randomised clinical trials of primary angioplasty have shown a reduced incidence of stroke,
recurrent ischaemia, and need for new target vessel revascularisation (TVR) compared to
fibrinolysis, even in low risk patients.
7
In selected subsets, primary angioplasty preserves left ven-
tricular ejection fraction
w4 w9
and benefits patients with anterior AMI treated up to 24 hour s after
symptom onset.
w10
The favourable effects on mortality and reinfarction appear to be more
pronounced among high risk patients, in particular those with haemodynamic evidence of
failure.
8
Benefits in this setting are also apparent from non-randomised data.
9
A quantitative over-
view by Weaver and colleagues
10
pooling 2606 patients showed that the mortality reduction
obtained with pr imary angioplasty compared to fibrinolysis was approximately 32% (table 4.1). If
this result can be reproduced everywhere, the magnitude of such treatment effect would be simi-
lar to that observed when fibrinolysis was used instead of placebo. However, these excellent results
*
20
derive from the experience of selected centres working under
the specific requirements of randomised investigation and
may not be easily achieved in the community setting, as is
suggested by the results of large national registries
9 w11 w12

The GUSTO II-B trial
7
addressed this particular issue by
testing the effect of angioplasty when performed mainly in
low volume centres on a low risk population. In fact, GUSTO
II-B showed a less favourable outcome of angioplasty than
expected from other trials, which was caused by a higher event
rateintheangioplastyarmratherthanbyalowereventrate
in the fibrinolysis arm. Furthermore, 36% of patients allocated
to fibrinolysis received an ang ioplasty before discharge, which
may blunt the differences between the two strategies at six
months. Crossover to angioplasty in patients initially ran-
domised to pharmacological treatment is a common and
important confounding factor when analysing differences in
long term outcome.
w11
Long term benefit of angioplasty has
been observed in the one year analysis of the SHOCK trial.
8
The mortality reduction obtained with the emergency
revascularisation strategy compared to the approach involving
initial medical stabilisation was not significant at 30 days
(46.7% v 56%, p = 0.11), but became so at six months (50.3%
v 63.1%, p = 0.027) and increased further at one year (55% v
70%, p = 0.008). Albeit a negative study statistically, the
number of lives saved per 1000 patients treated with the strat-
egy of emergency revascularisation is the highest ever
reported in a reperfusion trial (tables 4.1 and 4.2). The recent
availability of long term results of primary angioplasty trials
confirms the long lasting efficacy of the invasive approach also

in patients without haemodynamic failure, despite some initial
concern that early benefit may not be sustained
w13
(table 4.2).
NEW PERSPECTIVES IN REPERFUSION THERAPY
It is recognised that the success rate and durability of mechani-
cal revascularisation procedures and the efficacy and safety of
fibrinolytics have both improved. Primary angioplasty has been
Figure 4.1 Nearly all patients with
acute myocardial infarction (AMI)
could potentially benefit from
reperfusion treatment with
fibrinolytics, but less than 50% will
actually be treated; only 50–60% of
those will achieve a TIMI 3 grade
coronary flow, 10% will suffer from
early reocclusion, 1% will have a
stroke, and 20–30% will have late
reocclusion. On the other hand,
angioplasty can be offered to only
10% of patients with AMI, but more
than 90% of these will actually be
treated; 90% will achieve a TIMI 3
grade coronary flow, less than 5%
will have reocclusion, and less than
0.1% will have a stroke.
Availability Availability
Fibrinolysis Primary angioplasty
10%
5% Reocclusion

0.1% Stroke
>90% Treated
>90% TIMI 3
<50% Treated
54% TIMI 3
10% Reocclusion
1% Stroke
25% late
Occlusion
100%
50%
0%
0%
50%
100%
Table 4.1 Event rate at short term follow up, number needed to treat, and events avoided per 1000 patients treated in
randomised clinical trials comparing primary angioplasty and fibrinolysis.
30-day events PTCA (%, n) Lysis (%, n) p Value OR (95%CI) ARR% NNT NEA × 1000
Mortality
Weaver
10
4.4%, 57/1290 6.5%, 86/1316 0.02 0.66 (0.46 to 0.94) 2.1 47 21/1000
GUSTO II-B
7
5.7%, 32/565 7.0%, 40/573 0.37 0.80 (0.49 to 1.30) 1.3 77 13/1000
SHOCK
8
* 46.7%, 71/152 56%, 84/150 0.11 0.83 (0.67 to 1.04) 9.3 11 91/1000
C-PORT
w46

5.3%, 12/225 6.2%, 14/226 0.7 Not available 0.9 111 9/1000
DANAMI-2† 6.6%, 52/790 7.6%, 59/782 0.35 Not available 1.0 100 10/1000
Mortality or non-fatal reinfarction
Weaver 7.2%, 94/1290 11.9%, 156/1316 <0.001 0.58 (0.44 to 0.76) 4.7 21 48/1000
GUSTO-IIB 9.6%, 54/565 12.2%, 70/573 0.08 0.72 (0.49 to 1.05) 3.1 32 31/1000
C-PORT‡ 9.8%, 22/225 16.8%, 38/226 0.03 0.52 (0.30 to 0.89) 7 14 71/1000
DANAMI-2†‡ 8.0%, 63/790 13.7%, 107/782 0.0003 Not available 5.7 18 55/1000
Stroke
Weaver 0.7%, 9/1290 2.0%, 26/1316 0.007 0.35 (0.14 to 0.77) 1.3 77 13/1000
PAMI
w27
0 3.5%, 7/200 0.01 Not available 3.5 29 34/1000
Zijlstra
16
0.7%, 1/152 2.0%, 3/149 0.6 0.32 (0.01 to 4.08) 1.3 77 13/1000
GUSTO II-B 1.1%, 6/565 1.9%, 11/573 0.34 0.54 (0.17 to 1.63) 0.8 125 8/1000
C-PORT 1.3%, 3/225 3.5%, 8/226 0.13 Not available 2.2 45 22/1000
DANAMI-2† 1.1%, 8/790 2.0%, 15/782 0.15 Not available 0.9 111 9/1000
Haemorrhagic stroke
Weaver 0.1%, 1/1290 1.1%, 15/1316 <0.001 0.07 (0.0 to 0.43) 1 100 10/1000
PAMI 0 2.0%, 4/200 0.05 Not available 2 50 20/1000
Zijlstra 0.7%, 1/152 1.3%, 2/149 0.98 0.49 (0.01 to 9.47) 0.6 166 6/1000
GUSTO-IIB 0 1.4%, 8/573 0.007 Not available 1.4 71 14/1000
*The SHOCK trial did not compare PTCA with lysis, but a strategy of emergency revascularisation versus initial medical stabilisation.
†Data not published. Presented at the scientific sessions of the American College of Cardiology, March 2002.
‡Includes disabling stroke.
ARR, absolute risk reduction; NEA × 1000, number of events avoided per 1000 patients treated; NNT, number needed to treat.
ACUTE MYOCARDIAL INFARCTION: REPERFUSION TREATMENT
*
21

enhanced by the use of coronary stents
w14
and the av ailability of
glycoprotein IIb/IIIa inhibitors,
2
or the combined use of
both,
11 12 w15
while new fibrinolytic regimens offer better results
than those obtained with streptokinase or ev en with front
loaded rt-PA.
1w1w16
New infusive schemes
New fibrinolytic drugs are being developed and evaluated with
the aim of improving pharmacological reperfusion.
113w1w16
Initial studies suggested that lytic therapy may be as effective
as primary angioplasty.
w17
Efficacy
The combined use of fibrinolytics with glycoprotein IIb/IIIa
inhibitors appears encouraging at first glance. In the TIMI 14
trial
1
ahighrateofTIMI3flowgradewasobservedat90min-
utes after the infusion of 50 mg of alteplase and a full dose of
abciximab plus low dose heparin. This promising finding
relates to only 87 patients included in the dose finding and
dose confirmation phases of the study, which included angio-
graphyat90minutes.Outofthe34patientsstudiedinthe

dose finding phase, a TIMI 3 flow was observed in 22 patients
(76%), 3% of patients died, 3% suffered major bleeding, and
27% needed an urgent revascularisation procedure. Moreover,
59% of these patients underwent angioplasty before dis-
charge, 18% as an emergency rescue procedure.
TheIMPACT-AMItrial
w18
failed to detect a dose–response
relation using a combination of eptifibatide (Integrilin) and
100 mg of alteplase. On the contrary, the group treated with
eptifibatide had a tendency towards increased incidence of
in-hospital adverse events (51% v 39%) and mortality (11% v
0%),despiteasignificantlyhigherrateofTIMI3flowgradeat
90 minutes (66% v 39%). Despite the discrepancy between the
excellent angiog raphic results and the less impressive clinical
outcome in these small sized studies, these preliminary results
primed a new large scale trial which was recently published.
6
GUSTO V was powered to detect a 15% reduction in mortality
and randomised 16 588 patients to either standard lytic treat-
ment with reteplase or a combination of half dose reteplase
with full dose abciximab. The results obtained with the com-
bination therapy did not lower the mortality rate (5.6%) com-
pared to standard fibrinolysis (5.9%). Non-fatal complications
of AMI were significantly reduced, at the cost of higher rates
of non-intracranial bleeding. Thus, the relation between
patency and survival is not as straightforward as initially
anticipated; furthermore, the failure to reduce mortality in the
megatrials performed in this new era of reperfusion has
diverted attention to the reduction in non-fatal clinical events.

Drug delivery
Ease and speed of delivery of fibrinolytic drugs have been
improved with the use of a single bolus of mutant forms of
rt-PA. Recently, the results of two m egatrials (ASSENT-2 and
InTime-II) have been presented.
w19
Both studies confirmed
that the bolus injection of TNK-tPA and lanoteplase was as
effective as the long lasting infusion of rt-PA. However, lanote-
plase caused a significantly higher rate of intracranial bleeding
compared to rt-PA in InTime-II (1.13% v 0.62%, p = 0.003);
that was not the case for TNK-tPA (0.93%) when compared to
rt-PA (0.94%) in ASSENT-2.
Safety
Clinical studies aimed at assessing the efficacy and safety of
combinations of potent thrombolytic treatments have caused
thousands of intracranial bleeds.
w20
Furthermore, the inappro-
priate administration of a fibrinolytic agent may not be with-
out complications.
w21
Indeed, nearly 4.1% of patients who
receive fibrinolysis have non-coronary syndromes and the 30
daymortalityofthesepatientswas9.5%versus1.2%ofthose
allocated to placebo in the ASSET trial (p < 0.01).
w22
The
underutilisation of fibrinolytics in the real world as shown in
NRMI-2

w2
may reflect a certain “fear to treat”, particularly in
Table 4.2 Event rate at long term follow up, number needed to treat, and events avoided per 1000 patients treated in
randomised clinical trials comparing primary angioplasty and fibrinolysis
Long term events PTCA (%) Lysis (%) p Value Odds ratio (95% CI) ARR NNT NEA × 1000
Mortality
Weaver 6 months* 6.1 8.1 0.055 0.73 (0.52 to 0.98) 2 50 20/1000
PAMI 2 years
w29
6.2 9.5 0.21 Not available 3.3 30 33/1000
Zijlstra 5±2 years
16
13.4 23.9 0.01 0.54 (0.36 to 0.87) 10.5 10 100/1000
SHOCK 6 months
8
† 50.3 63.1 0.027 0.80 (0.65 to 0.95) 12.8 8 125/1000
SHOCK 1 year† 55 70 0.008 Not available 15 7 143/1000
C-PORT 6 months
w46
6.2 7.1 0.72 Not available 0.9 111 9/1000
Reinfarction
Weaver 6 months 4.4 9.7 0.0001 0.43 (0.3 to 0.6) 5.3 19 53/1000
PAMI 2 years 10.8 16.0 0.01 Not available 5.2 19 53/1000
Zijlstra 5±2 years 6 22 0.0001 0.27 (0.15 to 0.52) 6 6 167/1000
C-PORT 6 months 5.3 10.6 0.04 Not available 5.3 19 53/1000
Mortality or non-fatal reinfarction
Weaver 6 months 6.8 13.4 0.0001 0.47 (0.43 to 0.7) 6.6 15 67/1000
PAMI 2 years 14.9 23 0.034 Not available 8.1 12 83/1000
Zijlstra 5±2 years 22 46 0.0001 0.13 (0.43 to 0.91) 24 4 250/1000
C-PORT 6 months‡ 12.4 19.9 0.03 0.57 (0.34 to 0.95) 7.5 13 77/1000

New revascularisation
PAMI 2 years 32.8 54 0.001 Not available 21.2 5 200/1000
Zijlstra 5±2 years 46.4 71.1 <0.001 Not available 24.7 4 300/1000
Recurrence of ischaemia
PAMI 2 years 36.4 48 0.026 Not available 11.6 9 111/1000
Zijlstra 5±2 years 52 89.5 <0.001 Not available 37.5 3 333/1000
*Data on 2635 patients. Presented at the American Heart Association meeting in Atlanta, October 1999.
†The SHOCK trial did not compare PTCA with lysis, but a strategy of emergency revascularisation versus initial medical stabilisation.
‡Includes disabling stroke.
For explanation of abbreviations see table 1.
EDUCATION IN HEART
*
22
high risk patients. This concern will lead physicians to accept
the natural history of the disease rather than to prescribe the
reperfusion treatment that is available to most cardiologists,
which can be lifesaving, but will potentially induce a severe
complication. From a safety standpoint, lytic treatment may
therefore be perceived as being more hazardous than the
invasive approach.
Primary stented angioplasty and new antiplatelet
agents
The systematic use of coronary stents during primary
angioplasty was shown to reduce the incidence of reocclusion
and the need for new TVR compared to balloon dilatation. The
rate of TIMI 3 flow grade did not improve nor did systematic
stent implantation reduce the incidence of reinfarction and
mortalityinthelargeSTENT-PAMIandCADILLACtrials.
w14 w15
Similarly, initial experience with the use of IIb/IIIa receptor

inhibitors in association with primary angioplasty has yielded
contradictory results between some small studies
11 12
and the
larger RAPPORT
2
and CADILLAC trials.
w15
In RAPPORT, the use
of abciximab or placebo with primary ang ioplasty did not
affect the incidence of death, reinfarction or TVR at six
months; similarly, the CADILLAC trial yielded identical
incidence of the primary end point (mortality, reinfarction,
ischaemic TVR, and stroke) at six months in patients
undergoing stented angioplasty with or without administra-
tion of abciximab (11.5% and 10.2%, respectively). In both
studies, stent implantation offered better results than balloon
dilatation independently of the use of abciximab.
The concept of facilitated angioplasty or combined
“pharmaco-mechanical reperfusion” was evaluated by the
PACT investigators
3
; a bolus of 50 mg rt-PA or placebo was
givenonadmission,followedbyimmediateangiographyand
angioplasty unless TIMI 3 flow was observed. This use of fibri-
nolytic agents differs from the concept of “rescue angioplasty”
for failed lysis and, unlike rescue procedures, offers better
preservation of the left ventricular function without complica-
tions secondary to the lytic bolus. Although some benefit can
be expected from the combined form of reperfusion on “soft”

end points, such as preservation of left ventricular ejection
fraction and a reduced need for urgent TVR, there is no
evidence so far that this form of combined pharmaco-
mechanical strategy will reduce mortality or widen the
window of opportunity for reperfusion.
CONTEMPORARY ANGIOPLASTY AND
FIBRINOLYSIS: ARE THEY TRULY EQUIVALENT?
Whenever primary angioplasty and fibrinolysis are to be
evaluated as potentially equivalent,
w18
the following issues
should be considered.
Time delay
Setting up for and performing primary angioplasty requires
more time than starting an intravenous infusion. In ran-
domised clinical trials, the in-hospital delay in starting
fibrinolysis was on average 45–50 minutes shorter than the
time needed to start ang ioplasty.
10
The in-hospital procedure
related delay for primary angioplasty must be no longer than
90 minutes according to the American Heart Association/
American College of Cardiology recommendations.
w8
In nearly
90% of cases, the invasive strategy results in immediate TIMI
3flowgradeoftheinfarctrelatedartery,whilewithlytic
agents there is an additional delay before their effect starts. In
the TIMI-14 study
1

the administration of a bolus of alteplase
aloneorabolusfollowedbya30minuteinfusionofrt-PAand
abciximab was far less effective (TIMI 3 flow grade at 90 min-
utes: 48% and 62%, respectively) than the same bolus followed
bya60minuteinfusion(TIMI3flowgrade74%,p<0.02).
Even with the addition of abciximab, this indicates that the
concentration of the lytic agent must be maintained for at
least 60 minutes. Therefore, the time delay needed for the
optimallyticregimentobeeffectivemaybenotmuchshorter
than that for primary angioplasty.
Following primary angioplasty, a longer time delay could
resultinalargerinfarctsizeandalowerleftventricularejec-
tion fraction,
w23 w24
but apparently this does not adversely affect
the patency rate of the inf arct related artery or the six month
clinical outcome.
w23
Hospital mortality rates remain low and
predictable in patients treated within 12 hours of symptom
onset unless they present with cardiogenic shock.
14 w25 w26
On
the contrary, with lytic treatment, reperfusion rates decrease
and the mortality rates increase with increasing time, in par-
ticular beyond the third to fourth hour after symptom
onset.
514w27
Short term mortality strongly depends on the
quality and time frame of reperfusion.

15
Angioplasty yields a
higher degree of TIMI 3 flow grade than fibrinolysis and this
translates in a better short term outcome. Long ter m survival
largely depends on left ventricular function
516
; this in turn
depends on the extent of myocardial damage, which increases
as reperfusion is delayed. Thus angioplasty may be better for
patients admitted late—that is, more than four hours after
onset of symptoms
14
—in whom 30 day mortality with angio-
plasty remains under 5% but rises to over 12% with lysis.
w26 w28
Thetransportationofhighriskpatientstohospitalsoffering
invasive facilities should be considered since the additional
treatment delay does not seem to jeopardise the result of
mechanical reperfusion.
w23 w25 w26
Patients subgroups
Primary ang ioplasty applied to selected candidates may prove
more beneficial than its indiscriminate use, particularly in
patients with small low risk AMI. Available data support the
use of primary angioplasty over fibrinolysis in high risk
patients and in patients with haemodynamic impairment
(class I indication
w8
). Indirect data suggest that the mechani-
cal approach is a better alternative than fibrinolysis in clinical

subsets such as the elderly, patients with right ventricular
involvement, patients with AMI caused by the occlusion of
vein grafts, late presenters, or subjects who are ineligible for
Trial acronyms
ASSENT: Assessment of the Safety and Efficacy of a New
Thrombolytic regimen
CADILLAC: Controlled Abciximab and Device Investigation to
Lower Late Angioplasty Complications
DANAMI: Denish trial in Acute Myocardial Infarction
GUSTO: Global Use of Strategies to Open Occluded Coron-
ary Arteries in Acute Coronary Syndromes
IMPACT: Integrilin to Manage Platelet Aggregation in
Combatting Thrombosis
NRMI: National Registry of Myocardial Infarction
PACT: Plasminogen-activator Angioplasty Compatibility Trial
RAPPORT: Reopro and Primary PTCA Organization and Ran-
domized Trial
SHOCK: Should we emergently revascularize Occluded
coronary arteries for Cardiogenic shock?
STENT-PAMI: STENT Primary Angioplasty in Myocardial
Infarction
TIMI: Thrombolysis In Myocardial Infarction
ACUTE MYOCARDIAL INFARCTION: REPERFUSION TREATMENT
*
23
fibrinolysis. However, subgroup analysis should be considered
with caution since data fragmentation reduces the statistical
power and may cause type II errors. Proper randomised trials
are needed if these indications are to be fully legitimised.
Number needed to treat and number needed to harm

The demonstration of a significant reduction in mortality of
about 25% with fibrinolytic agents has required the random-
isation of more than 10 000 patients in each of the initial
studies. Later on, the GUSTO-I study
5
enrolled 41 021 patients
to obtain a further 14.6% risk reduction in mortality with
rt-PA versus streptokinase (95% confidence interval (CI) 5.9%
to 21.3%, p = 0.001). Equivalence trials have randomised
more than 31 000 patients to show that new fibrinolytic
agents “do not cause a clinically significant excess in
events”.
w19
Assuminga30daymortalityrateof7%inpatients
treated with fibrinolysis, about 12 000 patients would need to
be randomised to show a worthwhile 20% relative risk reduc-
tion with any alternative treatment. Primary angioplasty has
been shown to have f avourable effects on end points such as
mortality and reinfarction, even in smaller sized studies. These
considerations would support the contention that megatrials
on direct angioplasty are no longer necessary, but this position
has not gained universal acceptance.
Most potentially effective lytic drugs have been tested in
large clinical trials which were funded by companies with a
vested interest in orienting medical care at large. Regrettably,
there has not been enough interest to support prospective
randomised clinical trials comparing angioplasty and fibri-
nolysis that are large enough to provide unequivocal results.
The largest randomised study of this kind, GUSTO II-b,
included only 1138 patients and showed a non-significant

mortality reduction of 18.6%, resulting in 13 lives saved per
1000 patients.
7
A useful tool for the interpretation and comparison of out-
comes is the “number needed to treat” (NNT). NNT is
calculated as the reciprocal of the absolute outcome difference
between two treatment groups and offers an ingenious
measurement of the “therapeutic effor t to clinical yield” ratio.
The NNT to prevent one death, reinfarction, stroke or a
combined end point in the short term, according to the most
relevant trials compar ing angioplasty and fibrinolysis, is
shown in table 4.1. Similar calculations in regard to long term
results are given in table 4.2.
When using angioplasty instead of fibrinolysis in 1000
patients, 21 more lives would be saved and 13 stokes avoided
within the first month after AMI.
10
Even though the debated
32% mortality reduction obtained in the combined analysis of
these trials may not be representativ e of current practice, the
magnitude of the benefit obtained with angioplasty in the real
world seems at least as important as the benefit obtained with
front loaded rt-PA compared to streptokinase.
57
In GUSTO V the
absolute risk reduction in mortality was 0.3, resulting in 3 lives
sav ed per 1000 patients treated with combined therapy instead
of reteplase only (NNT = 333). Long term analysis shows that
angioplasty would sav e 20 more lives than fibrinolysis per 1000
patients at six months, 33 a t two years,

w29
and 100 at five
years.
16
Furthermore, 200 new TVRs would be prevented at two
years and 300 at five years after the index AMI.
A similar analysis can be applied to determine the adverse
effects of medical interventions (“number needed to harm”).
Out of 1000 patients treated with fibrinolysis, 8 would have
suffered from stroke in GUSTO II-B and 34 in PAMI (table
4.1). Such an event is fatal in 40% of patients and causes
severe morbidity in the remainder,
5
reducing the net clinical
benefit of fibrinolysis.
Applicability: the true frontier of reperfusion treatment
in the “real world”
Because the limitations to the applicability of each form of
reperfusion treatment are different, we believe that they rarely
present as an equivalent alternative.
The major limitation of primary angioplasty is the difficulty
in setting up the programme, performing the procedures in a
timely fashion, and reproducing the results of clinical trials.
However, a similar frontier exists for fibrinolytic treatment. In
the NRMI-2
w2
only 31% of the 272 651 patients analysed were
eligible for reperfusion, 3% had formal contraindications, 41%
presented after six hours, and 25% had non-diagnostic ECG;
furthermore, 24% of eligible patients were not given

reperfusion treatment. Not surprisingly, unadjusted mortality
in patients not receiving reperfusion treatment was nearly
three times higher than in treated patients. H ad angioplasty
been available, these patients could have benefited from
reperfusion treatment.
Results from the NRMI-2 study can be considered to be
representative of cardiology practice in the USA. Despite
differences between countries in eligibility criteria, time delay,
lytic agents, and treatment strategies, the major findings in
NRMI-2 are largely reproduced in Western Europe and
Canada, confirming the under utilisation of reperfusion treat-
ment. Overall fibr inolysis is given to only 66% of eligible
patients, and the use of invasive procedures ranges from 2.5–
11% of AMI patients between community and academic
institutions.
17
Among European countries, the UK has
reported the largest use of fibrinolytic agents: 71.6% of
patients with suspected AMI, ranging from 49–85% in differ-
ent hospitals,
w30
in the context of limited availability of
invasive facilities.
w31
Other countries use lytic agents less often,
perhaps in part because angioplasty is more readily available.
In Germany fibrinolysis is given in 36–42% of patients while
angioplasty is used in 10–25% of cases.
w32 w33
In France 37% of

AMI patients receive reperfusion treatment,
w34
either by means
of systemic lysis (32–45%) or angioplasty (13–43%).
w35 w36
Other reports from Israel, Italy, Scandinavia or Spain indicate
that fibrinolysis is given to 35–45% of patients.
17 w37–41
Data
from Australia and New Zealand state an eligibility rate of
53%, lytics being actually given in 43%, with a predominant
use of streptokinase (78%) over rt-PA (15.7%), and a growth in
surgery or angioplasty from 8.7% in 1986 to 17.4% in
1994.
w42 w43
Despite these differences in management of AMI
among western countries, there are no significant differences
in short term outcome,
w44
perhaps because the proportion of
reperfused patients is similar. Thus in daily practice, half of the
patients with AMI do not receive reperfusion treatment.
Reperfusion is rarely denied because of formal contraindica-
tions but usually because of late arrival, non-diagnostic ECG
changes, advanced age or other various reasons that raise a
“fear to treat” in about 25–35% of potentially eligible
cases.
17 w2 w44
Under all these circumstances, angioplasty, when
available, is not an “alternative” to lysis but the sole

opportunity for reperfusion. Paradoxically, the results of
angioplasty in this large patient subgroup, which represent an
ideal and undisputed setting for its use, are mostly un-
known.
w45
Therefore, increasing the availability of primary angio-
plasty, or shaping the triangle of fig 4.1 into a rectangle, would
be a worthwhile effort. As mentioned earlier, patient
transportationtohighworkloadtertiarycentresisasafeand
valuable therapeutic approach and, at least in theory, it may
proveamorerationalandcosteffectiveoptionthantheemer-
gence of a widespread network of low volume centres in which
EDUCATION IN HEART
*
24
optimal results may not be achieved. Such a strategy has been
investigated in a large randomised study in Europe (DANAMI-
2). The study randomly assigned AMI patients to front loaded
rt-PA or angioplasty in interventional centres, or to rt-PA ver-
sus transportation for angioplasty elsewhere in non-invasive
centres, and was prematurely stopped on 1 October 2001 after
a planned interim analysis because of the benefit observed in
the invasive strategy of the study (table 4.1). In the USA, a
recent small randomised trial has shown that the better
outcome of angioplasty over fibrinolysis can also be obtained
in community hospitals without on-site cardiac surgery.
w46
Which yardstick for measuring treatment effect?
If reperfusion strategies are considered as nearly equivalent,
then the accuracy of the measurement of their respective

effects becomes of major relevance. Randomisation is the best
tool for testing two treatment strateg ies; however, in this par-
ticular case, the method may have some pitfalls that must be
acknowledged. On the one hand, randomisation precludes
enrolment of patients who are ineligible for fibrinolysis. This
represents a group of patients at particularly high risk in
whom angioplasty is likely (but was not proven) to be benefi-
cial. On the other hand, double blinded analysis and outcome
adjudication is problematic. In patients assigned to angio-
plasty, information on coronary anatomy and ventricular
function is immediately available and complications may be
diagnosed and managed readily, leading to a more proactive
management of patients treated invasively.
ANCILLARY BENEFIT OF THE INVASIVE APPROACH
While the primary goal of any kind of reperfusion therapy is to
save lives by re-establishing effective myocardial perfusion,
some potential additional benefits are granted only with the
invasive approach. Admittedly, these ancillary benefits only
pertain to the few patients who have prompt access to the
invasive treatment.
The invasive approach enables the use of a variety of tools
such as stents, ultrasound imaging, thrombectomy or aspira-
tion devices, and provides the possibility of intracoronary or
local drug delivery, all of which may in the future prove to be
useful adjunctive agents to optimise reperfusion. Invasive
diagnostic tools may also help to gain additional insights into
the “mysteries” of reperfusion at the tissue level
18
—that is,
why one out of four patients who achieve a brisk epicardial

TIMI 3 coronary flow does not have tissue reperfusion.
w47
The immediate knowledge of the coronary anatomy and left
ventricular function facilitates accurate risk stratification and
allows the most appropriate individual treatment strategy to
be selected and implemented. New standards of care after
AMIhaveensuedandreducedthelengthofhospitalstayand
the need for further diagnostic testing.
w48 w49
Primary angioplasty is cost saving compared to
fibrinolysis.
19 w48 w49
This is mainly because of the lower
incidence of in-hospital reinfarction, recurrent ischaemia,
stroke, and shorter hospital stay.
w49
Late reocclusion of the infarct related artery with or without
reinfarction occurs in nearly 30% of patients after fibrinolysis
and bears a negative prognosis and a high mortality rate.
5w50
This likely explains the lack of survival benefit between fibr i-
nolysedandcontrolpatients10yearsafterdischargeinthe
GISSI study.
4w20
Conversely, with contemporary primary
angioplasty and stenting, reocclusion and reinfarction rates
are as low as 1–5%.
w14 w15
As has been determined from postmortem examination
w51

and has been recently confirmed in vivo,
w52
AMI may not
always be the consequence of a thrombotic coronary
occlusion. Acute events such as plaque rupture, spontaneous
dissections or intramural plaque haemorrhage associated with
spasm are the cause of AMI in nearly 30% of cases, a figure
which is close to the percentage of cases in which optimal lytic
therapy is ineffective.
1w17
Under those pathophysiological
circumstances, fibrinolysis and antiplatelet agents, even when
given at doses that go beyond their “safety ceiling”, will never
work, because the substratum on which these drugs act is
non-existent.
20
CONCLUSIONS AND FUTURE DIRECTIONS
Currently available evidence does not fully support the
contention that either the immediately invasive approach or
combined antithrombotic or pharmaco-mechanical strateg ies
are clearly superior to fibrinolysis in reducing mortality. We
need to learn from appropriately powered randomised clinical
trials whether or not primary angioplasty is beneficial when
applied to subgroups of patients who otherwise do not receive
reperfusion treatment. When appropriate, current guidelines
should be revised to incorporate specific recommendations for
these specific patient subsets.
In the meanwhile, primary angioplasty cannot be advocated
as the first therapeutic approach where it is not performed on
a regular basis by experienced operators. Reperfusion by lytic

treatmentremainsthetherapyofchoiceforAMIinmost
cases, although its efficacy and applicability in the real world
remain far from optimal.
Rather than taking a dogmatic approach to either form of
reperfusion treatment, percutaneous coronary intervention
and/or drugs should be used as needed to increase the overall
impact of reperfusion treatment in the community, taking
advantage of the best, locally available potential of each
approach.
13
The real challenge is to increase the proportion of
Reperfusion treatment for acute myocardial
infarction: key points
c
Reperfusion treatment for acute myocardial infarction
remains largely underused
c
Applicability of thrombolytic therapy and primary angio-
plasty is the major limitation to the use of reperfusion treat-
ment
c
Most recent efforts have aimed at “doing more for few
patients”. The real challenge is to “do more for more
patients”
c
Pre-hospital fibrinolysis shortens the duration of ischaemia
and increases myocardial salvage
c
Transportation of patients with acute myocardial infarction
to a catheterisation laboratory must be considered after

failed thrombolysis in high risk patients
c
Advantages of primary angioplasty are sustained in the long
term
c
Combined treatment with lytics and glycoprotein IIb/IIIa
inhibitors reduces complications, but not mortality
c
Combined use of pharmacological and mechanical reper-
fusion improves secondary clinical end points, but not
survival
c
Clinical trials in specific patient subsets are needed to estab-
lish the advantages of primary angioplasty
c
A tailored reperfusion strategy based on the risk profile at
presentation may prove more rational than their indiscrimi-
nate use in the few patients who have access to all resources
ACUTE MYOCARDIAL INFARCTION: REPERFUSION TREATMENT
*
25
patients with AMI receiving reperfusion treatment and to “do
more for more patients” rather than “do more for fewer
patients”. Pre-hospital diagnosis and treatment of AMI are
important. At a time when mortality from AMI has decreased
to lower levels, pre-hospital treatment will likely be the only
waytoreducemortalityanyfurther.Immediatetreatment
with lytic and/or antiplatelet drugs and transportation for
angioplasty seem to be the most rational approach. Prompt
restoration of coronary flow and subsequent intervention

should optimise tissue reperfusion and avoid coronary
reocclusion.
3w53
Transfer of selected patients to a centralised,
high volume invasive service while reperfusion is continuing
would render angioplasty applicable to a much larger patient
population, shorten the duration of ischaemia, and increase
the potential for myocardial salvage. Such an approach will
occur when both the availability of percutaneous coronary
intervention services is increased and these resources are used
to treat high risk patients. To treat all AMI patients with half
doses of expensive lytic agents, full doses of very expensive
glycoprotein IIb/IIIa inhibitors, stents, aspiration and protec-
tion devices, followed by conventional drug treatment, would
not be sensible. The available reperfusion tools should be
applied selectively, tailored to the patient’s risk profile and
temporal presentation, as shown in fig 4.2.
There is at present little scientific evidence supporting this
“common sense” line of action for the future. Widespread use
of glycoprotein IIb/IIIa inhibitors in combination with lytics
and an increase in the availability of invasive facilities will
have a major impact on treatment costs that need to be
weighed against the expected incremental reduction in
mortality and postinfarction heart failure.
ACKNOWLEDGEMENT
The authors wish to thank the staff of cardiologists from their institu-
tions for the opinions and suggestions that contributed to the prepa-
ration of this manuscript, in particular Dr Antonello Vado, from the
Ospedale Santa Croce for statistical assistance. Dr F Ribichini was
supported in part by a Research Fellowship of the European Society of

Cardiology.
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c Large reperfusion trial that showed a significant (14.6%) risk
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streptokinase.
6 GUSTO V Investigators. Reperfusion therapy for acute myocardial
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therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V
randomised trial.
Lancet
2001;357:1905–14.
c The most recent megatrial of infusive reperfusion treatment in AMI
that compared standard fibrinolysis with reteplase versus half dose
of reteplase plus full dose of abciximab. The study showed identical
mortality rates with both treatments.
7 GUSTO II-b Angioplasty Substudy Investigators. A clinical trial
comparing primary coronary angioplasty with tissue plasminogen activator
for acute myocardial infarction.
N Engl J Med
1997;336:1621–8.
c The largest randomised trial that compared primary angioplasty
with accelerated rt-PA in AMI in community hospitals. The
advantages of primary angioplasty were marginal and not
sustained at six months.
8 Hochman JS, Sleeper LA, Webb JG,
et al
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Early revascularization in acute myocardial infarction complicated by
cardiogenic shock.
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9 Tiefenbrunn AJ, Chandra NC, French WJ,
et al
. Clinical experience with
primary transluminal coronary angioplasty compared with alteplase
(recombinant tissue-type plasminogen activator) in patients with acute
myocardial infarction: a report from the second national registry of
myocardial infarction (NRMI-2).
J Am Coll Cardiol
1998;31:1240–5.
c National registry that analyses the clinical outcome of 272 651
patients with AMI presenting at US hospitals. Very low percentage
of patients eligible for reperfusion therapy (31%); similar results
with lysis and angioplasty. Angioplasty is superior in patients
presenting in cardiogenic shock.
10 Weaver DW, Simes JR, Betriu A,
et al
. Comparison of primary coronary
angioplasty and intravenous thrombolytic therapy for acute myocardial
infarction. A quantitative review.
JAMA
1997;278:2093–8.
c Meta-analysis of all available randomised trials that compared
fibrinolysis and primary angioplasty. The invasive strategy
significantly reduces mortality by 32%.
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et al

for the Stent versus
Thrombolysis for Occluded Coronary Arteries in Patients with Acute
Myocardial Infarction Study Investigators. Coronary stenting plus platelet
glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator
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N Engl J Med
2000;343:385–91.
12 Montalescot G, Barragan P, Wittenberg O,
et al
. Platelet glycoprotein
IIb/IIIa inhibition with coronary stenting for acute myocardial infarction.
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Engl J Med
2001;344:1895–903.
13 White HD. Future of reperfusion therapy for acute myocardial infarction.
Lancet
1999;354:695–7.
c Brief but complete summary of recent trials and thoughtful
considerations about the future of reperfusion treatment.
14 Brodie BR. When should patients with acute myocardial infarction be
transferred for primary angioplasty? [editorial].
Heart
1997;78:327–8.
c Comparison of differences of outcome according to time to
reperfusion with primary angioplasty or fibrinolysis from the
extrapolation of data from PAMI and GUSTO I trials respectively.
15 GUSTO Angiographic Investigators. The effects of tissue plasminogen
activator, streptokinase, or both on coronary-artery patency, ventricular
function and survival after acute myocardial infarction.
N Engl J Med

1993;329:1615–22.
16 Zijlstra F, Hoorntje JCA, de Boer MJ,
et al
. Long-term benefit of primary
angioplasty as compared with thrombolytic therapy for acute myocardial
infarction.
N Engl J Med
1999;341:1413–19.
Figure 4.2 Streptokinase can still be used as a first choice
treatment in low risk patients (as currently done in many patients
treated in South America, UK, Australia, New Zealand, and the
Netherlands), while patients presenting with higher clinical risk
would benefit from the use of the more expensive recombinant tissue
plasminogen activator (t-PA). The combination of recombinant t-PA
and a glycoprotein IIb/IIIa inhibitor (abciximab) will reduce the
clinical complications of acute myocardial infarction, but will not
reduce mortality. Rescue angioplasty (PTCA) can be reserved for
high risk patients who did not achieve reperfusion or have a poor
clinical course. Primary angioplasty should be preferred for patients
presenting with haemodynamic failure, advanced age (> 75 years)
or presenting late (more than 4–5 hours after symptom onset). The
previous administration of half doses of lytic treatment is desirable
when it can be given out of hospital by first aid providers, or in the
emergency department when access to the catheterisation laboratory
is delayed. The use of stents and glycoprotein IIb/IIIa inhibitors
during angioplasty does not reduce mortality. Instead of being used
indiscriminately, these tools should be considered in unfavourable
patient or lesion subsets, such as in the presence of a large
thrombotic burden after wire crossing or suboptimal flow after
angioplasty.

Streptokinase
Baseline risk of death
L
e
v
e
l

o
f

a
g
g
r
e
s
s
i
v
e
n
e
s
s

o
f

T

x
t-PA
t-PA + llb-llla i
t-PA+llb-llla+PTCA
PTCA rescue
PTCA primary
EDUCATION IN HEART
*
26
c Impressive demonstration of the superiority of primary
angioplasty over fibrinolysis on survival at long term follow up
(5±2 years).
17 Venturini F, Romero M, Tognoni G. Patterns of practice for acute
myocardial infarction in a population from ten countries.
EurJClin
Pharmacol
1999;54:877–86.
18 Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal
reperfusion during acute myocardial infarction?.
Circulation
1993;88:1361–74.
c Excellent editorial review that addresses the discrepancies between
the complete degree of angiographic epicardial reperfusion and
tissue reperfusion.
19 Parmley WW. Cost-effectiveness of reperfusion strategies.
Am Heart J
1999;138:S142–6.
20 O’Neill WW. Coronary thrombosis during acute myocardial infarction:
Roberts was right!
Am J Cardiol

1998;82:896–7.
c Interesting observations about the non-thrombotic origin of a
number of total acute coronary occlusions that may not be relieved
by lytic agents.
Additional references appear on the
Heart
website–
www.heartjnl.com
ACUTE MYOCARDIAL INFARCTION: REPERFUSION TREATMENT
*
27
5 OFF-PUMP CORONARY ARTERY
BYPASS SURGERY
Peter P Th de Jaegere, Willem J L Suyker
C
oronary revascularisation plays an important role in the management of patients with
ischaemic heart disease. Its principle builds on restoring antegrade flow thereby relieving
angina. As a result, the need for medication is reduced which, in turn, may improve quality
of life and socioeconomic independency. Also the prognosis is beneficially affected. This is not only
true for patients with severe coronary atherosclerosis such as patients with left main or three vessel
disease, but also for patients with less advanced disease.
w1–3
c
WHY OFF-PUMP BYPASS SURGERY?
The first milestones in coronary revascularisation were surgical. It all started after the second world
war with the implantation of the internal mammary artery indirectly into the cardiac muscle (the
Vineberg procedure). A few years later, procedures for direct coronary artery revascularisation were
designed, initially including endarterectomy, followed by the construction of an anastomosis
between a donor artery or vein and the coronary ar tery. Interestingly, these first operations were
performed on the beating heart without the use of extracorporeal circulation and cardiac arrest.

w4
The results of these early initiatives were generally unpredictable, preventing general acceptance
and widespread use. It became clear that the safety and efficacy of surgical coronary revascularisa-
tion in terms of in-hospital complications and immediate and long term clinical outcome greatly
depends, among other factors, on the quality of the anastomosis between the donor graft and
recipient coronary artery. To predictably create these delicate and very precise hand sewn anasto-
moses, the surgeon needs a still and bloodless field with full exposure of the target area, enabling
the required complex and coordinated manipulation of the microsurgical instruments.
In this respect, the introduction of cardiopulmonary bypass (CPB) and cardiac arrest by Faval-
oro in 1967 proved to be a tremendous step forward. Because basic surgical requirements could now
be properly addressed, consistent high quality anastomoses could be produced by the broad major-
ity of cardiac surgeons. Indeed, the reported excellent clinical outcome and long term results initi-
ated a tremendous increase in the number of bypass operations reaching the clinical status of “gold
standard”. Earlier efforts using different techniques were completely overwhelmed and almost for-
gotten for nearly 30 years. Excellent long term clinical results have been reported in a wide variety
of patients, especially when using the internal mammary artery.
w5 w6
The superiority of coronary
artery bypass grafting (CABG) with the use of CPB and cardiac ar rest—the so-called conventional
CABG—with respect to angina reduction and the need for repeat revascularisation, in comparison
with medical treatment and percutaneous transluminal coronary angioplasty (PTCA), is subject to
little discussion.
w6–8
As a result, conventional bypass surgery has been quoted as “safe, effective,
durable, reproducible, complete, versatile and teachable”.
w9
The question, however, is whether bypass surgery with CPB and cardiac arrest is indeed safe.
Data from the National Cardiac Surgery Database of the Society of Thoracic Surgery encompassing
170 895 patients are summarised in table 5.1.
w10

Overall, the proportion of patients suffering no
complications was only 64.3%.
1
In addition, health insurance data and data from clinical studies
disclose that 10.2% do not leave the hospital within 14 days after the operation and 3.6% of the
patients are discharged to a non-acute care facility.
2w11
The scope of the problem becomes clear
when one considers that bypass surgery is performed in approximately 800 000 patients/year
worldwide. Conventional bypass surgery is increasingly being questioned and this has stimulated
the quest for novel surg ical techniques guaranteeing the good results of precise direct coronary
revascularisation, but avoiding factors believed to adversely affect the outcome and, thus, leading
to less perioperative morbidity, faster recovery, shorter hospital stay, and reduced costs. One of these
factors may be the use of cardiopulmonary bypass.
In this paper, the clinical experience and the reasons why isolated, off-pump surgery m ay lead to
improved outcome are addressed. Off-pump surgery is defined as CABG surgery on the beating
heart without the use of CPB and cardiac arrest, irrespective of the surgical access to the heart. Iso-
lated bypass surgery implies coronary bypass surgery without concomitant cardiac or vascular pro-
cedures at the time of bypass grafting.
*
28
DETERMINANTS OF PERIOPERATIVE MORBIDITY
AND MORTALITY
Surgical risk is influenced by a number of patient related fac-
tors such as age, severity of coronary artery disease, left ven-
tricular function, and the presence of comorbid conditions (for
example, diabetes, renal insufficiency, pulmonary and periph-
eral vascular disease, obesity). On the basis of these
demographic and clinical determinants, risk models have
been developed which can be used to either calculate the sur-

gical risk or to stratify patients into low, medium or high risk
subgroups.
34
In addition to these patient related factors—which unfor tu-
nately cannot be corrected but, at best, may be modified or
optimised before surgery—a number of procedure related fac-
tors play a role (table 5.2). In case of conventional bypass sur-
gery, access to the heart must be obtained via full sternotomy,
the heart and ascending aorta are cannulated for CPB, cardiac
arrest is induced, and the ascending aorta is manipulated for
the construction of a proximal anastomosis in case of saphen-
ous vein or free arterial grafts. All these steps contribute to
patient trauma and are likely to be associated with potential
complications or may provoke biological reactions. Given their
technical nature, there is ample room for improvement or
innovation.
Central to the discussion is the use of CPB and the classical
midsternal split. CPB requires the cannulation of the heart
and the ascending aorta which may induce atherosclerotic
(micro)emboli. Intraoperative transcranial Doppler monitor-
ing has disclosed that the highest embolic load of the brain
occurs during the aortic manipulation in preparation of CPB.
5
During a later stage of the operation, these emboli may not
consist of particulate matter but rather of air bubbles
introduced into the circuit by retrieving spilled blood from the
surgical field or imperfections in the connections despite the
useofarteriallinefilters.
5
The magnitude of the embolic load

correlates with the duration of CPB and is reflected by the
severity of postoperative cerebral dysfunction. Given these
findings, it is conceivable that avoidance of CPB will substan-
tially decrease the risk of perioperative neurolog ic complica-
tions, especially in elderly and other high risk patients. Yet, to
completely avoid aortic manipulation, bypass surgery on the
beating heart should also entail the exclusive use of in situ
mammary grafts. For extensive coronary artery disease, more
complex techniques like graft interposition between an in situ
mammary artery and a coronary artery may be needed to
obviate the need for aortic side clamping. Recently, automated
vessel coupling systems suitable for connecting saphenous
vein grafts to the aorta have started to become available. While
still unproven, these systems may enable safe anastomoses on
the ascending aorta in the future, simplifying the surgical
procedure. Elderly patients in particular may benefit from off-
pump, no-aortic touch bypass surgery since the incidence of
atherosclerosis of the ascending aorta—and thus the risk of
emboli—increases with age.
3w12
In addition to the risk of microemboli, CPB induces a total
body inflammatory response caused by the activation of the
complement system due to contact of the blood with the arti-
ficial surface of the CPB circuit.
6w13
All organs are affected to a
varying degree, potentially leading to dysfunction and/or
damage of the brain, lungs, heart itself, bowel, kidneys, and
coagulation system. Although the role of CPB in this response
has been established and a whole body of evidence indicates

that avoidance of CPB reduces oxidative stress, inflammation,
and perioperative morbidity, it must be stressed that other
factors such as the trauma of the surgical incision and the use
of anaesthesic drugs may contribute to this inflammatory
response as well.
w14–17
Thus, changes in surgical access to the
heart, anaesthesiology, and pharmacology during the off-
pump bypass may lead to a reduction in inflammation and
postoperative morbidity.
As opposed to the heart, CPB produces a non-pulsatile flow
which is thought to have an adverse effect on the microcircu-
lation, leading to arteriolar shunting. This may contr ibute to
postoperative organ dysfunction or failure.
w18
Non-pulsatile
flow is one of the mechanisms which, in combination with the
inflammatory response and the release of free radicals, is
thought to be responsible for postoperative renal f ailure.
7
Irrespective of the exact pathophysiology of CPB induced
postoperative morbidity and mortality, these side effects have
revitalised the nearly forgotten art of off-pump bypass
surgery. The increasing public awareness of these complica-
tions and of less invasive alternative techniques in coronary
revascularisation (PTCA) and other fields of surgery contrib-
utetothisnewimpetus.
Off-pump surgery on the beating heart also offers the
opportunity to reduce the surgical incision and trauma to
skin, soft tissue, and bone. Smaller access by means of various

forms of minithoracotomy may reduce the risk of peri-
operative infection and enhance the speed of recovery.
Sternotomy requires 6–12 weeks to heal and prevents early
return to normal daily activities.
w19
Deep sternal wound infec-
tion occurs in 1–4% of the patients and is associated with a
25% mortality.
3
The determinants of deep sternal wound
infections are obesity, the presence of diabetes, renal failure,
redo surgery, and a number of operator related variables such
as the use of more than one mammary artery and excessive
use of electrocautery. Unfortunately, some of these risk f actors
such as obesity may not be compatible with reduced access
Table 5.1 Perioperative complications during
isolated CABG (%)
First
operation Reoperation
Number of patients 157159 13736
Mortality 2.6 7.3
Myocardial infarction 1.1 3.4
Reoperation 4.6 7.4
For bleeding 2.2 3.1
Stroke 2.4 3.1
Permanent 1.7 2.2
Transient 0.7 0.8
Pulmonary
Prolonged ventilation (>24 hours) 5.3 10.2
Oedema 1.9 3.4

Pneumonia 2.2 3.8
Acute distress syndrome 1.4 1.8
Renal failure 2.9 5.2
Dialysis required 0.8 1.7
Gastrointestinal complications 2.3 3.0
Multiorgan failure 0.6 1.4
Infection 4.9 6.0
Sternal 1.3 1.5
Leg 1.3 1.5
Urinary tract 1.4 1.4
Sepsis 0.9 1.6
Modified from Borst and Gründeman.
w10
CABG, coronary artery bypass graft surgery.
OFF-PUMP CORONARY ARTERY BYPASS SURGERY
*
29
type operations because of the prohibitive surgical difficulty of
constructing a coronary anastomosis. The most benefit of a
limited approach will probably be obtained in patients with
diabetes, renal failure or redo heart surgery, provided that
thesepatientsdonothavethreevesseldiseasesupplying
viable myocardial tissue. In such a situation, full sternotomy
may be more appropriate. A disadvantage of a minithora-
cotomy, however, is the increased amount of postoperative
pain, especially when costal cartilages are traumatised as a
result of substantial traction for surgical exposure or when
multiple incisions are performed.
w20
NOVEL APPROACH, NEW PROBLEMS

The potential advantages of a novel surgical approach, in this
case off-pump bypass surgery, must be weighed against novel
technical problems and limitations (table 5.3).
As stated before, the quality of the coronary anastomosis
must be guaranteed. In the early days of off-pump bypass sur-
gery, motion of the target area was controlled by pharmaco-
logic reduction of global myocardial contractility and/or heart
rate, with or without some primitive for m of regional stabili-
sation by means of traction sutures. The breakthrough,
however, came with the introduction of advanced regional
mechanical stabilisers such as the CardioThoracic Systems
Ultima device and the Utrecht Octopus in the mid 1990s.
8w14
These devices consistently reduced the motion of the target
area sufficiently to offer workable conditions for the majority
of the surgical community. These stabilisers are, respectively,
compressive and suction type devices that are fixed to one side
of the operating table or chest wall retractor, with the other
end apposed to the epicardial surface. As a result the coronary
artery anastomosis can be constructed with enough surgical
comfort and allow graft patency rates comparable to conven-
tional CABG.
w10
Not surprisingly this has augmented the
number of off-pump bypass operations from a neglig ible
number in 1995 to 10% in 1999, and is expected to be 50% by
2005.
w21
Yet, to construct a coronary anastomosis safely, the surgeon
also needs a bloodless field. Therefore, the flow of the recipient

coronary artery must be temporarily interrupted. For this pur-
pose, vessel snares (suture or silicone elastomer tape) or
atraumatic vascular clips are used proximally and often also
distally to the coronary arteriotomy. This is invariably associ-
ated with myocardial ischaemia. Although generally well tol-
erated, it may occasionally provoke arrhythmia and haemody-
namic instability, eventually necessitating conversion to
on-pump bypass surgery and cardiac arrest. The interruption
of the flow of the right coronary artery is known to provoke
these complications. This can be addressed by placing an
intracoronary shunt or seal when performing the anastomo-
sis.
w22 w23
Although unproven, these mechanical solutions, as
well as the coronary sutures or clips, all add to endothelial
damage which may contribute to the development of late
luminal narrowing.
1w24
In addition, the clinical value of shunts
is questioned since they may be cumbersome to use and, with
respect to the shunt, blood flow through the shunt is only
30–50% of the native coronary flow.
1
Ensuringadry,bloodlessfieldmayalsobehinderedbyback
bleeding from perforating septal branches in the vicinity of the
arteriotomy. This can be addressed by frequent blotting, inter-
mittent saline infusion, or the use of high flow carbon dioxide
moisturised insufflation.
9
It will be clear that, as opposed to

conventional CABG, the off-pump surgeon needs an innova-
tive and more flexible attitude to create optimal conditions
consistently during surgery.
Haemodynamic instability and a drop in systemic blood
pressure may occur when compressing or luxating the heart.
Little displacement is required when reaching the left anterior
and diagonal arteries. This is not the case when the circumflex
or right coronary artery needs to be grafted. A nearly vertical
displacement may be needed for the posterior wall, which is
obtained by either deep pericardial traction stitches or a sling
or a supporting device.
w25
Such a notable displacement is sur-
prisingly well tolerated in most patients, but can provoke a
significant drop in blood pressure and myocardial flow.
10 w26
Patients with left ventricular hypertrophy or poor ventricular
function may not tolerate such a manoeuvre.
w25
Yet these
patients are potentially ideal candidates for off-pump bypass
surgery since a slight depression of myocardial contractility,
induced by global ischaemic cardiac arrest during bypass sur-
gery with CPB, may prohibit weaning from CPB or may lead to
a low output syndrome which is the most common cause of
operative mortality.
3w27
Generally, all regions of the heart can
be reached in the great majority of patients by perfect
placement of the traction stitches and by improving venous

Table 5.2 Steps in conventional bypass surgery, consequences and potential
solutions
Surgical trauma Consequence(s) Solution
Access to the heart Recovery time Minithoracotomy
Full sternotomy Infection (e.g.mediastinitis) Port-access surgery
Endoscopic robotic CABG
Cardiopulmonary bypass Manipulation heart and aorta Off-pump CABG
(microemboli)
Inflammatory response
Cardiac arrest Cell injury, necrosis Off-pump CABG
Side clamping Microemboli No-touch aorta surgery
Aorta ascendens (in situ arterial grafting)
(graft interposition)
For details see text.
Clinical issues to be considered in CABG
c
Effectively relieves angina (palliation)
c
May positively affect event-free survival (prognosis)
c
Non-negligible perioperative morbidity
c
Cardiopulmonary bypass plays a major role in the
pathophysiology of the perioperative morbidity
c
Novel approaches such as off-pump beating bypass surgery
are being proposed
EDUCATION IN HEART
*
30

return by utilising the Trendelenburg position with or without
additional fluid load and inotropic support.
w25
Conventional bypass surgery via full sternotomy and CPB
with a decompressed and arrested heart provides sufficient
visibility and space to construct safely and adequately an
anastomosis on all coronary arteries. This may be more diffi-
cult in limited access approaches and off-pump bypass
surgery. Moreover, limited visibility may also interfere with
identification of the target coronary artery. Therefore, training
and patient selection are crucial in off-pump bypass surgery to
optimise the learning curve. The left anterior descending, dis-
tal right, and proximal posterior descending arteries are rela-
tively easy to approach with a limited anterior thoracotomy or
subxyphoidal incision. Full sternotomy may be the most opti-
mal approach for patients with three vessel disease.
Still experimental are the advanced robotic instruments
capable of increasing surgical dexterity sufficiently to enable
thorascopic bypass surgery, preferably with the aid of three
dimensional visualisation.
w28
These systems have not yet
provided the breakthrough of total endoscopic CABG
(TECAB) mainly because of the still substantial technical dif-
ficulty in creating a robot-sewn anastomosis. Currently, inter-
est seems to be shifting towards alternative, automated ways
of performing the distal coronary anastomoses. While glued
anastomoses certainly hold promise, most advancement has
been in the area of mechanical connecting systems such as
small, intraluminal stent-like structures, intraluminal mag-

nets, and extraluminal devices with small hooks. While these
connectors are already available for the larger, proximal anas-
tomosis on the aorta, the relatively small size of the coronary
arteries and their delicate, friable walls impose large obstacles
forthedevelopmentofreliablesystemsthatmayultimately
enable TECAB in large groups of patients.
CLINICAL EXPERIENCE
The clinical experience with off-pump bypass surgery is sum-
marised in table 5.4. These data should be interpreted with
caution since all but one originate from non-randomised
observations made by pioneers in the field. Therefore selection
bias, time bias, observation bias, and publication bias cannot
be ruled out. Also, there is quite some variation in the defini-
tion of the outcome measures and in the consistency and
methods of the acquisition of the clinical events between the
studies. Taking into account these limitations, these data sug-
gest that perioperative mortality and morbidity following off-
pump bypass surgery compares favourably with those of the
National Cardiac Surgery Database summar ised in table 1.
Only one study conducted at the University Medical Center
Utrecht, using the Octopus Tissue Stabilizer, directly com-
paredoff-andon-pumpbypasssurgerybymeansofa
randomised clinical trial.
11 12
This study revealed, however, no
superiority in 30 day clinical outcome and only a modest
superior cognitive outcome at three months which became
negligible at 12 months after off-pump bypass surgery.
12
Taking into account the expectations of off-pump bypass

surgery, these findings were somewhat disappointing. The
study, however, was conducted in patients of whom 50% had
two vessel disease with a normal ventricular function and
little comorbidity. This is also reflected by the low incidence of
complications in patients who underwent on-pump bypass
surgery. Two findings, however, favour off-pump CABG: there
was a reduced need for blood products in the off-pump group,
and there was a 41% reduction in postoperative creatine
kinase MB release. The former is a consistent finding in most
of the observational studies summarised in table 5.4. The lat-
ter suggests that avoiding CPB reduces the degree of myocar-
dial necrosis which is in accordance with a significant reduc-
tionintroponinIreleaseinoff-pumppatientsreported
previously.
13 14
Apparently local ischaemia during clamping of
the coronary arteries is less har mful than global cardiac
ischaemia. The clinical importance of this finding is that post-
operative elevation of cardiac markers of necrosis has been
identified as an independent correlate with one year clinical
outcome.
w29
Information on long term results of off-pump CABG is
derived from the cases studies cited above (table 5.4) and the
randomised clinical trial we directed at the University Medical
Center Utrecht. Again, taking into account the limitations of
Table 5.3 Disadavantages and technical limitations of off-pump coronary artery
bypass surgery
Technical issues Proposed solutions
Motion of the heart Pharmacologic or mechanical stabilisation

Tempory interruption of coronary flow Luminal shunt during construction of anastomosis
Arteriotomy seal
Distal perfusion cannula
Blood flow in arteriotomy Temporary luminal shunt
Saline infusion
Carbon dioxide gas blower
Pressure drop Trendelenburg, inotropic support, fluid
Limited space for: Miniaturisation of instruments
preparation of mammary artery Endoscopic video assisted surgery
identification of coronary artery
construction of anastomosis
Determinants of perioperative morbidity
c
Age
c
Extent of coronary artery disease
c
Ventricular function
c
Comorbid conditions
c
Extent of the surgical trauma
c
Use of cardiopulmonary bypass
c
Global ischaemic cardiac arrest
c
Manipulation and instrumentation of the ascending aorta
OFF-PUMP CORONARY ARTERY BYPASS SURGERY
*

31
the observational studies, survival free from myocardial
infarction after off-pump bypass surgery compares favourably
with off-pump surgery. A striking feature is a higher
occurrence of angina pectoris after off-pump bypass surgery
and a higher frequency of percutaneous revascularisation
during the follow up period.
4
This may be explained by less
complete revascularisation and, thus, the lear ning curve of
this surgically more demanding operation. This was not
observed in the randomised clinical tr ial we conducted (Natho
H, et al, unpublished data).
With respect to graft patenc y, data from observational stud-
ies in comparison with historical controls suggest similar early
graft patency between off-pump (91–99 %) and on-pump
(94–99%) bypass surgery.
15 16
THE FUTURE
Doctors together with their patients now have a therapeutic
spectrum of myocardial revascularisation procedures. At one
end there is plain balloon PTCA which is the least invasive
modality, followed by stents and other more advanced novel
catheter technologies, and adjunctive pharmacologic and
genetic intervention. The other end of the spectrum consists of
bypass surgery. The most invasive approach, conventional
CABG via full sternotomy, is now being challenged by full and
limited access off-pump CABG. The slightly disappointing
absence of notably better early clinical outcome after
off-pumpCABGdrawsourattentiontothegapinthe

spectrum. This place could be filled by TECAB, the perfect
intermediate between percutaneous techniques and current
surgery. While not possible for mainstream clinical use yet,
this could change within a time frame of as little as five years.
In the meantime, the trend towards better clinical outcome,
however slight, should urge surgeons to expand carefully the
use of off-pump techniques and limited size incisions
whenever possible.
REFERENCES
1 Duhaylongsod F. Minimally invasive cardiac surgery defined.
Arch Surg
2000;135:296–301.
2 Roach G, Kanchuger M, Mangano C,
et al
. Adverse cerebral outcomes
after coronary bypass surgery.
N Engl J Med
1996;335:1857–63.
c Observational study reporting the frequency of permanent stroke
and transient neurologic dysfunction after conventional bypass
surgery. The paper indirectly puts into perspective the potential role
of off-pump bypass surgery.
3 Eagle K, Guyton R, Davidoff R,
et al
. ACC/AHA guidelines for coronary
artery bypass graft surgery.
J Am Coll Cardiol
1999;34:1262–347.
c Extensive report and summary of the American Heart
Association/American College of Cardiology guidelines on bypass

surgery: history, complications, outcome, and determinants.
4 Arom K, Flavin Th, Emery R,
et al
. Safety and efficacy of off-pump
coronary artery bypass grafting.
Ann Thorac Surg
2000;69:704–10.
c Retrospective analysis of the immediate outcome of 350 patients
treated in a single centre. Patients were stratified into three risk
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provides insights into the potential role of off-pump bypass surgery.
5 Mark D, Newman M. Protecting the brain in coronary artery bypass graft
surgery.
JAMA
2002;287:1448–50.
6 Edmunds L. Why cardiopulmonary bypass makes patients sick: strategies
to control the blood-synthetic surface interface.
Adv Cardiac Surg
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c Landmark paper on the role of cardiopulmonary bypass in the
perioperative morbidity, providing insight into the pathophysiology
and, thus, potential solutions.
7 Ascione R, Lloyd C, Underwood M,
et al
. On-pump versus off-pump
coronary revascularization: evaluation of renal function.
Ann Thorac Surg
1999;68:493–8.
c Small randomised clinical trial assessing the changes in renal
function after off- and on-pump surgery. The protective effects of

off-pump surgery are demonstrated.
8 Borst C, Jansen E, Tulleken C,
et al
. Coronary artery bypass grafting
without cardiopulmonary bypass and without interruption of native
coronary flow using a novel anastomosis site restraining device
(“Octopus”).
J Am Coll Cardiol
1996;27:1356–64.
c Experimental study in a pig model explaining the function of the
Octopus tissue stabiliser and the histologic effects on the
myocardium after application.
9 Stanbridge R, Hadjinikolaou L. Technical adjuncts in beating heart
surgery. Comparison of MIDCAB to off-pump sternotomy: a meta-analysis.
Eur J Cardiothorac Surg
1999;16(suppl 2):S24–33.
10 Grundeman P, Borst C, van Herwaarden J,
et al
. Hemodynamic changes
during displacement of the beating heart by the Utrecht Octopus method.
Ann Thorac Surg
1997;63:S898–92.
c Experimental study disclosing the potential adverse haemodynamic
effects during the manipulation of the heart during off-pump
Table 5.4 In-hospital and 30 day clinical events after off-pump bypass surgery
Author (ref) Year Number of patients Death CVA AMI RF Inf Redo AF
Subramanian
w26
1997 182 3.8 0.5 3.8 nr 2.7 3.2 8.0
Sternik

w27
1997 64 3.1 1.6 3.1 nr nr nr nr
Diegeler
w30
1998 209 0.5 nr 1.9 nr nr 2.4 nr
Jansen
w31
1998 100 0.0 2.0 4.0 nr 1.0 1.0 12.0
Magovern
w19
1998 60 0.0 0.0 nr nr nr 1.7 nr
Tasdemir
w32
1998 2052 1.9 0.8 2.9 0.2 0.5 0.9 17.0
Calafiore
w33
1999 122 0.0 0.0 0.0 nr nr 0.8 9.8
Arom
4
2000 350 3.4 1.4 0.6 5.0 nr 2.8 14.0
Cartier
w34
2000 300 1.3 1.6 4.0 nr 4.6 5.0 30.0
Koutlas
w12
2000 53 0.0 2.2 0.0 0.0 0.0 0.0 26.0
Hart1
17
2000 1582 1.0 0.6 1.3 0.9 0.3 1.2 15.0
Varghese

w35
2001 35 2.9 nr 2.9 5.7 nr nr 23.0
Yeatman
w36
2001 75 1.3 0.0 2.7 6.7 0.0 2.7 12.0
Hernandez
18
2001 1754 2.5 1.3 nr nr nr 4.5 21.0
Puskas
19
2001 200 1.0 1.5 1.0 nr 0.0 1.5 nr
Van Dijk (39) 2002 142 off-p 0.0 0.7 4.9 0.0 5.0 4.0 20.0
139 on-p 0.0 1.4 4.3 1.0 5.0 2.0 21.0
All events are expressed as percentage.
AF, atrial fibrillation; AMI, acute myocardial infarction; CVA, cerebrovascular accident; Inf; infection; nr, not reported; off-p, off-pump coronary artery
bypass surgery, on-p, on-pump coronary artery bypass surgery; Redo, postoperative rethoracotomy for bleeding, infection or graft revision;
RF, postoperative new renal failure.
Expectations and potential limitations of off-pump
bypass surgery
c
No need for cardiopulmonary bypass
c
Reduction of surgical trauma
c
Reduction of perioperative morbidity, recovery time,
hospital stay, and costs
c
Limited access, motion of the heart
c
Quality of the anastomosis

c
Haemodynamic changes, inducing organ dysfunction and
reducing applicability
c
Completeness of revascularisation
EDUCATION IN HEART
*
32
bypass surgery—a problem which can be adequately addressed but
may still limit the use of off-pump bypass surgery.
11 Van Dijk D, Nierich A, Jansen E,
et al
. Early outcome after off-pump
versus on-pump coronary bypass surgery. Results from a randomized
study.
Circulation
2001;104:1761–6.
c First multicentre randomised clinical trial comparing off- and
on-pump bypass surgery. Detailed surgical data and clinical
outcome at 30 days are reported.
12 Van Dijk D, Jansen E, Hijman R,
et al
. Cognitive outcome after off-pump
and on-pump coronary artery bypass graft surgery. A randomized trial.
JAMA
2002;287:1405–12.
c Multicentre randomised clinical trial comparing off- and on-pump
bypass surgery. Neurologic outcome and detailed information on
neurocognitive dysfunction and outcome at three months are
reported.

13 Ascione R, Lloyd CT, Gomes WJ,
et al
. Beating versus arrested heart
revascularization: evaluation of myocardial function in a prospective
randomized study.
Eur J Cardiothorac Surg
1999;15:685–90.
c Small, single centre, randomised clinical trial assessing the
protective effects of off-pump bypass surgery in comparison to
on-pump surgery on myocardial cell damage and loss.
14 Kilger E, Pichler B, Weis F,
et al
. Markers of myocardial ischemia after
minimally invasive and conventional coronary operation.
Ann Thorac Surg
2000;70:2023–8.
c Non-randomised study assessing the course of the serum markers
of myocardial tissue damage during off- and on-pump surgery
through various routes of cardiac access. Off-pump surgery is
associated with less injury in comparison with on-pump surgery.
15 Mack M, Osborne J, Shennib H. Arterial graft patency in coronary artery
bypass grafting: what do we really know?
Ann Thorac Surg
1998;66:1055–59.
16 Mack M, Magovern J, Acuff T,
et al
. Results of graft patency by immediate
angiography in minimally invasive coronary artery surgery.
Ann Thorac
Surg

1999;68:383–90.
c A prospective, observational study reporting graft patency after
LIMA insertion on the left anterior descending artery during
off-pump surgery.
17 Hart J, Spooner T, Pym J,
et al
. A review of 1,582 consecutive Octopus
off-pump coronary bypass patients.
Ann Thorac Surg
2000;70:1017–20.
c A succinct and concise summary of the clinical outcome of a large
series of patients who underwent off-pump bypass surgery with the
Octopus method in seven centres in the USA and Europe.
18 Hernandez F, Cohn W, Baribeau Y,
et al
. In-hospital outcomes of
off-pump versus on-pump coronary artery bypass procedures: a multicenter
experience.
Ann Thorac Surg
2001;72:1528–34.
c Indirect comparison of the in-hospital outcome between 1741
patients who underwent off-pump bypass surgery with 6126 patients
who underwent conventional bypass surgery in four centres of the
Northern New England Cardiovascular Disease Study Group.
19 Puskas J, Thourani V, Marshall J,
et al
. Clinical outcomes, angiographic
patency and resource utilisation in 200 consecutive off-pump coronary
bypass patients.
Ann Thorac Surg

2001;71:1477–84.
Additional references appear on the
Heart
website–
www.heartjnl.com
OFF-PUMP CORONARY ARTERY BYPASS SURGERY
*
33
6 MANAGEMENT OF CARDIOGENIC
SHOCK COMPLICATING ACUTE
MYOCARDIAL INFARCTION
Venu Menon, Judith S Hochman
T
he incidence of cardiogenic shock in community studies has not decreased significantly over
time. Despite decreasing mortality rates associated with increasing utilisation of revasculari-
sation, shock remains the leading cause of death for patients hospitalised with acute myocar-
dial infarction (MI). Although shock often develops early after MI onset, it is typically not
diagnosed on hospital presentation. Failure to recognise early haemodynamic compromise and the
increased early use of hypotension inducing treatments may explain this observation.
Recently, a randomised trial has demonstrated that early revascularisation reduces six and 12
month mortality.
12
The current American College of Cardiology/American Heart Association
(ACC/AHA) guidelines recommend the adoption of an early revascularisation strategy for patients
< 75 years of age with cardiogenic shock.
3
In this article, we review the incidence, aetiology, pre-
vention, and recognition of shock, as well as its management.
c
INCIDENCE

The extent of myocardial salvage from reperfusion treatment decreases exponentially with time to
re-establishing coronary flow. Unfortunately, there has been little progress in reducing time to
hospital presentation over the past decade,
4
and this perhaps accounts for the stagnant incidence
of cardiogenic shock in community studies (7.1%).
5
Cardiogenic shock also complicates non-ST
elevation acute coronary syndromes. The incidence of shock in the PURSUIT trial was 2.9%
(1995–97),
6
similar to the 2.5% incidence reported in the non-ST elevation arm of the GUSTO II-B
trial (1994–95).
7
A number of strategies that centre on reducing the time to effective treatment may
help decrease the incidence of shock. These include public education to decrease the time to hos-
pital presentation, triage and early transfer of high r isk patients to selected centres, and early pri-
mary percutaneous coronary intervention (PCI) or rescue PCI for failed thrombolysis in high risk
patients.
PREDICTING AND PREVENTING SHOCK
The onset of cardiogenic shock in a patient following ST elevation MI heralds a dismal in-hospital
prognosis. The 7.2% of patients developing shock in the GUSTO-I trial accounted for 58% of the
overalldeathsat30days.
8
Similarly, the 30 day death rates with non-ST elevation MI cardiogenic
shock in the PURSUIT and GUSTO-II b databases were 66% and 73%, respectively. Even with early
revascularisation, almost 50% die at 30 days. The prevention of shock is therefore the most effec-
tive management strategy. The opportunity for prevention is substantial, given the observation that
only a minority of patients (10–15%) present to the hospital in cardiogenic shock. Whether due to
pump failure or a mechanical cause, shock is predominantly an early in-hospital complication in

the ST elevation MI setting. The median time post-MI for occurrence of shock in the randomised
SHOCK tr ial was 5.0 (interquartile range 2.2–12) hours. Similarly, median time from MI onset to
development of shock in the SHOCK registry was 6.0 (1.8–22.0) hours, and median time from hos-
pital admission was 4 hours. Shock complicating unstable angina/non-Q MI occurs at a later time
period. In the GUSTO-IIb trial shock was recognised at a median of 76.2 (20.6–144.5) hours for
non-ST elevation MI compared to 9.6 (1.8–67.3) hours with ST elevation MI (p < 0.001), and
median time to shock in the non-ST elevation PURSUIT trial was 94.0 (38–206) hours.
A primary goal in preventing shock should be an effort to reduce the large proportion of patients
presenting with acute ST elevation MI who do not receive timely reperfusion treatment. Successful
early reperfusion of the infarct related coronary artery while maintaining integrity of the
downstream microvasculature limits ongoing necrosis, salvages myocardium, and may prevent the
development of shock in many vulnerable patients. In-hospital development of shock often follows
failed thrombolysis or successful thrombolysis followed by evidence of recurrent MI (ST
re-elevation), infarct extension (ST elevation in new leads), and recurrent ischaemia (new ST
depression). These complications may be significantly reduced by a primary PCI strategy. Currently,
aminorityofhospitalsintheUSAandanevensmallerproportionworldwidepossessthe
infrastructure and personnel to perform primary PCI effectively.
*
34
Recognising patients at highest risk for development of
shock may facilitate the early transfer of high risk patients
before onset of haemodynamic instability. Early referral of
high risk patients for rescue angioplasty in the setting of
thrombolytic failure may also prove beneficial.
A number of scoring systems using predictive models for
the development of shock have been reported to aid with this
decision strategy. In the GUSTO-I study, age, systolic blood
pressure, heart rate, and presenting Killip class accounted for
> 85% of the predictive information. The same four variables
were significant in the GUSTO III population and accounted

for > 95% of the predictive information, with a validated con-
cordance index of 0.796.
9
Major predictors of shock in the
PURSUIT population included age, systolic blood pressure, ST
depression on presenting ECG, heart rate, height, enrolling
MI, and rales on physical examination. Although these scoring
systems can be useful, the limitations of these databases need
to be stressed. Patients enrolled in randomised clinical trials
are themselves selected. Furthermore, positive predictive
value for a patient with maximum attainable scores in the
GUSTO-I and PURSUIT model are only 50% and 35%,
respectively.
10
CLINICAL RECOGNITION
Treatment cannot be initiated unless the clinical entity is rec-
ognised. Cardiogenic shock is characterised by inadequate tis-
sue perfusion in the setting of adequate intravascular volume.
Specifically, shock in the peri-infarction setting is defined as
sustained hypotension (systolic blood pressure < 90 mm Hg
for > 30 minutes), accompanied by signs of peripheral hypo-
perfusion (altered mental status, cool peripheries, oliguria).
This clinical entity is unresponsive to fluid resuscitation alone,
with a cardiac index < 2.2 l/min/m
2
. Subjects requiring phar-
macologic or mechanical circulatory support to maintain
blood pressure are also included in this category. However,
thereisawidespectrumofclinicalsymptoms,signs,and
haemodynamic findings and variability in the severity of

shock. It should be diagnosed in all patients exhibiting signs
of inadequate tissue perfusion irrespective of blood pressure.
Some patients, particularly those with anterior MI, develop
signs of end organ hypoperfusion in the setting of unsup-
ported blood pressure measurements > 90 mm Hg. The urine
output is typically low and the heart rate > 90 beats per
minute. This “pre-shock” presentation is associated with a
high risk of in-hospital morbidity and mortality (43%).
11
When the physician fails to recognise that the tachycardia is
caused by a pronounced reduction in stroke volume and
therefore administers β blockers, frank shock may be precipi-
tated.
In the SHOCK trial registry, 64% of patients presented typi-
cally with hypotension, evidence of ineffective cardiac output
(resting tachycardia, altered mental status, oliguria, cool
peripheries), and pulmonary congestion.
12
A substantial
minority (28%) presented with evidence of hypoperfusion in
the absence of pulmonary congestion—the “silent lung” syn-
drome. These latter patients have an equal distribution of
anterior (50%) and non-anterior index infarctions (50%) with
pulmonary capillary wedge pressure in the range of
21.5±6.7 mm Hg. Inexperienced clinicians may inappropri-
ately treat such patients with large fluid boluses akin to the
management of hypotension with right ventr icular
infarction.
13 14
Unadjusted in-hospital mortality for this group

in the SHOCK registry exceeded that for the classical presen-
tation (70% v 60%, p = 0.036), a difference that was
non-significant after adjustment. These data highlight the
clinical importance of the subjective signs of hypoperfusion
obtained on physical examination in this population. In the
GUSTO-I mortality model, altered sensorium (odds of dying
1.68, 95% confidence intervals (CI) 1.19 to 2.39), cold clammy
skin (odds of dying 1.68, 95% CI 1.15 to 2.46), and oliguria
(odds of dying 2.25, 95% CI 1.61 to 3.15) were associated with
an increased 30 day mortality independent of haemodynamic
variables.
15
AETIOLOGY
There are several possible causes of cardiogenic shock in the
setting of MI–left ventricular dysfunction, right ventricular
dysfunction, and mechanical complications (fig 6.1). Recogni-
tion of shock should immediately lead to a quest for its cause.
A combination of the history, physical findings, ECG, and a
screening echocardiogram (table 6.1) will enable the clinician
to arrive quickly at an accurate diagnosis. A right heart cath-
eterisation is often not necessary for diagnosis and need only
be performed when there is continued doubt or to guide man-
agement when shock does not rapidly resolve. Predominant
left ventricular pump failure in the setting of a large MI is the
most common aetiology. Ventricular septal rupture, severe
mitral regurgitation, cardiac rupture, and tamponade should
be excluded and haemorrhagic shock considered, especially in
the elderly. Although the typical findings of significant right
ventricular infarction are hypotension, clear lung fields, and
jugular venous distension, severe right ventricular dysfunc-

tion (with or without excess fluid administration) may result
in left ventricular compromise caused by right ventricular dis-
tension and septal shift, resulting in clinical evidence of
pulmonary congestion. Systolic anterior motion of the
anterior mitral leaflet causing left ventricular outflow tract
obstruction in the MI setting has also been reported. Other
masqueraders in this situation include aortic dissection and
massive pulmonary embolism, which should be considered in
the appropriate clinical context. The latter includes discord-
ance between extent of ECG and haemodynamic
abnormalities—that is, mild to moderate ECG abnormalities
in the setting of severe haemodynamic derangement.
MANAGEMENT OF CARDIOGENIC SHOCK CAUSED
BY PREDOMINANT LEFT VENTRICULAR FAILURE
Reports of dramatic declines in mortality with early revascu-
larisation for cardiogenic shock began to emerge in the late
1980s.
16–18
Dedicated investigators in selected centres reported
these single centre observations which were, however, prone
to selection and publication bias. Randomised clinical trials
testing the superiority and generalisability of an early
Trial acronyms
DIGAMI: Diabetes mellitus Insulin Glucose infusion in Acute
Myocardial Infarction
FTT: Fibrinolytic Therapy Trialists
GUSTO: Global Utilization of Streptokinase and Tissue
plasminogen activator for Occluded coronary arteries
PURSUIT: Platelet glycoprotein IIb/IIIa in Unstable angina:
Receptor Suppression Using Integrilin Therapy

SHOCK: SHould we emergently revascularize Occluded
Coronaries for cardiogenic shocK ?
SMASH: Swiss Multicenter trial of Angioplasty for SHock
MANAGEMENT OF CARDIOGENIC SHOCK COMPLICATING ACUTE MYOCARDIAL INFARCTION
*
35
revascularisation strategy were clearly warranted and the
National Heart, Lung, and Blood Institute funded the SHOCK
trial in the USA, while the SMASH tr ial in Switzerland evalu-
ated the same issue.
19 20
WhileSMASHfailedtorecruitan
adequate number of patients, SHOCK reported an increase in
30 day survival from 46.7% to 56.0% by the adoption of an
early revascularisation strategy, but this absolute 9% differ-
ence did not reach significance (p = 0.11). On follow up, the
survival difference in favour of the early revascularisation
strategy became larger and significant at six months (36.9% v
49.7%, p = 0.027) and one year (33.6% v 46.7%) for an abso-
lute reduction of 13.2% (95% CI 2.2% to 24.1%, p < 0.03). The
Kaplan-Meier survival curves for the early revascularisation
and initial medical stabilisation arms are illustrated in fig 6.2.
There were 10 prespecified subgroup variables examined,
including sex, age, prior MI, hypertension, diabetes, anterior
MI, early or late shock, and transfer or direct admission status.
A benefit of early revascularisation was demonstrated for all
subgroups except for the elderly. Age > 75 versus < 75 years
interacted significantly with treatment effect at 30 days, six
months, and one year. The benefit of early revascularisation
waslargeforthose<75yearsat30days(41.4%v 56.8%, 95%

CI −27.8% to −3.0%), and six months (44.9% v 65.0%, 95% CI
−31.6% to −7.1%) and was not apparent for the elderly (see
below). An increased utilisation of revascularisation was also
associated with improved outcome in the GUSTO-I thrombo-
lytic trial and favourable outcomes in recent registries.
21 22
An
algorithm for the management of cardiogenic shock is
outlined in fig 6.3.
Step 1: immediate resuscitation measures
The goal is to prevent devastating end organ injury while the
patient is being transported for definitive treatment. Mainte-
nance of adequate mean arterial pressure to prevent adverse
neurologic and renal sequelae is vital. Dopamine or noradren-
aline (norepinephrine), depending on the degree of hypoten-
sion, should be initiated promptly to raise mean arterial pres-
sure and be maintained at the minimum dose required.
Dobutamine may be combined with dopamine at moderate
doses or used alone for a low output state without frank hypo-
tension. Intra-aortic balloon counterpulsation should be initi-
ated before transportation when facilities are available.
Arterial blood gas and oxygen saturation should be monitored
with early institution of continuous positive airway pressure
or mechanical ventilation as needed. The ECG should be
monitored continuously, and defibrillating equipment, intra-
venous amiodarone, and lidocaine should be readily available.
(Thirty three per cent of patients in the early revascularisation
arm of the SHOCK trial had cardiopulmonary resuscitation,
sustained ventricular tachycardia or ventricular fibrillation
before randomisation.) Transcutaneous pacing electrodes as

well as provisions for temporary transvenous pacing should be
placed at the patient’s bedside. Aspirin and full dose heparin
should be administered. For ST elevation MI requiring trans-
fer for angiography, we recommend intra-aortic balloon pump
(IABP) placement at the local hospital when possible. A fibri-
nolytic agent should be initiated in patients with ST elevation
MI if the anticipated delay to angiography is more than two
hours. Thirty five day mortality for patients with systolic blood
pressure < 100 mm Hg receiving thrombolysis in the FTT
meta-analysis was 28.9% compared to 35.1% with placebo.
This translates into 62 lives saved (95% CI 26 to 98, p < 0.001)
per 1000 patients treated.
23
Augmentation of blood pressure
with an IABP in this situation may facilitate thrombolysis by
increasing coronary perfusion pressure. Similarly, raising
blood pressure (to 130 mm Hg systole) by using vasopressor
support has also shown synergism in experimental models,
but this increase is difficult to achieve in patients in shock. For
Figure 6.1 Aetiology of suspected cardiogenic shock in the
combined SHOCK trial registry and trial (total n = 1422, only first
232 trial patients are included). “Other” includes shock caused by
prior severe valvar disease, dilated cardiomyopathy, excess β
blockade/calcium channel blockade, haemorrhage, and procedural
complications. Aortic dissection, pulmonary embolism, and dynamic
subaortic outflow obstruction should also be considered. LVF, left
ventricular function; MR, mitral regurgitation; RVF, right ventricular
failure; VSR, ventricular septal rupture.
80
LVF

70
Aetiology of shock
Contribution (%)
60
50
40
30
20
10
0
VSR
MR
Isolated RVF
Tamponade
Other
Table 6.1 Usefulness of echocardiography in
cardiogenic shock
c Evaluate left ventricular function and myocardium at risk
c Evaluate remote myocardial segments
c Screen for ventricular septal rupture
c Screen for severe mitral regurgitation and proceed to
transoesophageal echocardiography as needed
c Look for tamponade/rupture
c Assess right ventricular function
c Look for aortic dissection
Figure 6.2 Kaplan-Meier curve showing 12 month survival in the
early revascularisation and initial medical stabilisation arms of the
SHOCK trial. Reproduced from Hochman
et al
,

2
with permission of
the American Medical Association.
1.0
0.8
Time from randomisation (months)
Early revascularisation (n = 152)
Medical treatment (n = 149)
12
1086420
Proportion alive
0.6
0.4
0.2
0.0
EDUCATION IN HEART
*
36
non-ST elevation MI cardiogenic shock awaiting catheterisa-
tion, a glycoprotein IIb/IIIa inhibitor should be initiated.
Step 2: early definition of coronary anatomy
This is the pivotal step in the management of cardiogenic
shock resulting from predominant ischaemic pump failure.
Patients in a community hospital setting should be emer-
gently transferred/airlifted to an experienced designated
regional tertiary care facility. The referring and accepting phy-
sician as well as the critical care transport team should be in
constant communication to avoid delays in cardiac catheteri-
sation. Prophylactic IABP placement is recommended before
transfer and otherwise before angiography; radiocontrast use

should be minimised. Early reversal of hypotension with IABP
support serves as an excellent prognostic marker for survival,
butthosewhodoordonotrespondwelltoIABPbothderive
benefit from early revascularisation. If a high quality echocar-
diogram has already been performed, a ventriculogram need
not be repeated. Shock is characterised by a high incidence of
triple vessel disease, left main disease, and impaired left ven-
tricular function.
24
The mean (SD) left ventricular ejection
fraction for patients in the SHOCK trial and registry was 29
(11)% and 34 (14)%, respectively. The extent of ventricular
dysfunction and haemodynamic instability should be corre-
lated with coronary anatomy. An isolated circumflex lesion or
a right coronary lesion should rarely manifest as shock in the
absence of right ventricular infarction, left ventricular under-
filling, bradyarrhythmia or prior MI or cardiomyopathy. In
situations like this it is important for the clinician to immedi-
ately consider and exclude mechanical and other aetiologies of
cardiogenic shock.
Step 3: perform early revascularisation
Definition of anatomy should be followed rapidly by selection
of the modality of revascularisation. PCI will most often be the
treatment of choice. Glycoprotein IIb/IIIa antagonists and
stenting of the infarct related artery are indicated, although
trial data are lacking. Recent reports suggest an additive ben-
efit of stenting and glycoprotein IIb/IIIa antagonists in cardio-
genic shock similar to the remainder of the clinical spectrum
of PCI.
25

However, if there is sluggish flow despite absence of
post-coronary angioplasty stenosis, we recommend waiting
until flow normalises before stenting. Stenting may exacer-
bate distal embolisation. Glycoprotein IIb/IIIa antagonists
may improve reflow. Intracoronary adenosine or nitroprusside
may be tried. There is no randomised clinical evidence to sup-
port multivessel angioplasty in this setting, and the decision to
perform angioplasty in the non-infarct related artery should
be individualised. In selected cases, with remote ischaemia,
Figure 6.3 Algorithm on management of cardiogenic shock following ST elevation myocardial infarction. AS, atrial stenosis; CABG,
coronary artery bypass graft; CAD, coronary artery disease; IABP, intra-aortic balloon pump; LAD, left anterior descending; LBBB, left bundle
branch block; LV, left ventricle; MR mitral regurgitation; MS, mitral stenosis; PTCA, percutaneous transluminol coronary angioplasty; RV, right
ventricle; VSR, ventricular septal rupture. Reproduced from Topol EJ (ed)
Textbook of cardiovascular medicine
, 2nd ed, with permission.
Assess volume status
Treat sustained arrhythmias - brady or tachy
Mechanical ventilation, as needed
– correct acidaemia
– correct hypoxaemia
Inotropic/vasopresser support (dopamine)
Acute massive ST /
extensive evolving Q's
or new LBBB
Cath lab immediately
available
Yes
Yes
Aspirin, heparin
Rapid IABP

No
No
Pump failure
RV, LV, both
Acute severe MR
VSR
Critical AS/MS
Aortic dissection
tamponade
Emergency echo/
colour flow Doppler
Operating room
±
coronary angiography
e.g. no ST
limited ST /Q's
delayed CS
Cath lab
Coronary angiography ±
left ventricular angiography
Pulmonary artery catheterisation
PTCA for 1, 2 or moderate 3 vessel CAD
GP IIb/IIIa antagonist
Coronary stent
Cardiac surgery
CABG for severe 3 vessel or left main LAD
Correct mechanical lesions ± CABG
ST
Lytic
No ST

Gp IIb/IIIa
,
MANAGEMENT OF CARDIOGENIC SHOCK COMPLICATING ACUTE MYOCARDIAL INFARCTION
*
37
non-infarct related artery critical stenosis, and lack of haemo-
dynamic improvement after infarct related artery PCI (with
IABP support), revascularisation of the non-infarct territory
may play a role. In patients with moderate three vessel disease,
emergent PCI of the infarct related artery with consideration
for later coronary artery bypass graft surgery (CABG) is
preferred based on the concern that distal embolisation in
non-infarct related artery segments is not tolerated in shock.
There are no trials randomising patients to PCI versus
CABG in the setting of cardiogenic shock. The safety and fea-
sibility of CABG in this situation is well documented. Severe
triple vessel and left main coronary artery disease with
severely impaired left ventricular function predominate in the
shock setting. Emergent CABG allows the opportunity to
achieve complete revascularisation and rectify severe mitral
regurgitation while cardiopulmonary bypass maintains sys-
temic perfusion. The SHOCK trial protocol recommended
emergency CABG for patients with left main or severe three
vessel disease. The in-hospital mortality rates with CABG in
the SHOCK trial and registry were the same as the outcomes
with PCI despite more severe coronary artery disease and
twice the rate of diabetes in patients who underwent CABG
(fig 6.4). We believe that CABG is under used in the shock set-
ting. When dictated by anatomy, we recommend emergent
CABG with pre-induction IABP support. The potential for

benefit with metabolic support in this situation is large but
remains formally untested in the shock setting.
Intra-aortic balloon counterpulsation support
Consistent with the current ACC/AHA guidelines, we recom-
mend early consideration of IABP placement for patients with
cardiogenic shock who are candidates for an aggressive strat-
egy. Although randomised controlled trial data are lacking,
benefit is seen across a number of observational databases.
26–29
It provides excellent temporary haemodynamic support in
many patients.
30
It must also be noted that in the randomised
SHOCK trial use of IABP was strongly recommended in both
the early revascularisation and conservative arm. IABP
utilisation was 87% in this trial and may have contributed to
the improved outcomes observed in both groups compared to
historical controls. The observed rates of IABP utilisation in
US sites increased from 35% in GUSTO-I to 47% in GUSTO-III
(p = 0.001).
31
In contrast, utilisation at non-US sites in both
trials were low (7% and 10%, respectively). We believe that
IABP is currently underutilised in the setting of shock and
strongly recommend that community hospitals attempt to
develop an IABP programme so that treatment may be
initiated before transfer whenever possible.
ISSUES IN SHOCK MANAGEMENT
How should the elderly be treated?
Although there was no apparent benefit from an early revas-

cularisation strategy in patients aged > 75 years in the
SHOCK trial, the total number of patients in this subgroup
was small (n = 56). The 17% of 277 patients aged > 75 years
in the concomitant SHOCK registry who were selected for
early revascularisation appeared to derive benefit that was
similar to their younger counterparts, even after covariate
adjustment.
32
We do not feel there is adequate evidence to cat-
egorically deny early revascularisation to the elderly. We use an
individualised approach to the elderly. A select group based on
prior functional status, “physiologic” age, comorbidity, prox-
imityofMI,durationofshock,andcoronaryanatomymaybe
offered an early revascularisation strategy. In the absence of
contraindications, the remainder are treated with thrombo-
lysiswithorwithoutIABP,orcomfortcarealoneforthose
unlikely to benefit (see below). The very elderly often request
comfort care alone.
Is there a therapeutic window for emergency
revascularisation?
Early revascularisation should be considered as soon as possi-
ble following diagnosis of cardiogenic shock. The median time
from randomisation to revascularisation was 1.4 (0.6–2.8)
hours and the median time from MI to randomisation was 11
hours in the randomised SHOCK trial. However, it should be
notedthatpatientswereeligibleforthetrialifshockwas
diagnosed within 36 hours of index MI and randomisation
performed within 12 hours of shock onset. There was no sig-
nificant interaction between time from MI to randomisation
and treatment effect. Ongoing ischaemia and stuttering

necrosis are typical in the vicious cycle of ischaemia–
hypoperfusion that characterise shock. Unlike primary reper-
fusion treatment, the window of opportunity in this setting is
large. We recommend an early revascularisation strategy for
shock patients up to 48 hours post-index MI and up to 18
hours post-shock. Patients who are not revascularised within
18 hours of shock onset but survive the early phase with reso-
lution of shock should undergo coronary angiography. Revas-
cularisation should be performed based on standard post-MI
criteria—that is, triple vessel or left main disease or spontane-
ous or inducible ischaemia.
What is the quality of life?
Although the SHOCK trial showed that 13 lives were saved at
one year per 100 patients treated with an early revascularisa-
tion strategy, it was important to document that survivors had
an acceptable quality of life. It is reassuring that 83% of one
year survivors (n = 90) were in New York Heart Association
heart failure functional class I or II at 12 months.
Is care ever futile?
It is difficult to assess futility in the acute critical setting that
characterises cardiogenic shock. It is vital to establish
communication with the family as soon as the clinical entity is
recognised. The patient or surrogate should play a role in the
decision making process. Patients who require prolonged car-
diopulmonary resuscitation and sustain presumed anoxic
brain damage and those with other life shortening illnesses
are not candidates for aggressive care. Although cardiac index,
blood pressure, signs of hypoperfusion, and ejection fraction
are independently associated with outcome, the beneficial
effect of early revascularisation was noted across the spectrum

of subgroups, except the very elderly. Further research is
Figure 6.4 In-hospital mortality with percutaneous coronary
intervention (PCI) and coronary artery bypass graft surgery (CABG)
in the early revascularisation arm of the randomised SHOCK trial
compared to the non-randomised larger SHOCK registry.
PCI
CABG
50
40
45%
42%
45.5%
27.9%
Trial
In-hospital mortality (%)
Registry
30
20
10
0
EDUCATION IN HEART
*
38
required to develop a r isk score to identify other patients with
very poor outcomes despite early revascularisation. This may
enable effective resource utilisation in the future and prevent
heroic manoeuvres for patients unlikely to benefit.
MANAGEMENT OF MECHANICAL COMPLICATIONS
The utilisation of early reperfusion strategies has decreased
the incidence of mechanical complications post ST-elevation

MI.
33 34
Overall incidence of ventricular septal rupture in the
GUSTO-I tr ial was 0.2% (84/41021) with a 30 day mortality of
73.8%.
35
Although IABP may help achieve temporary haemo-
dynamic stability, prognosis following onset of haemodynamic
collapse is grim.
36
The overall in-hospital mortality for
ventricular septal rupture complicated by cardiogenic shock in
the SHOCK registry was 87% (47/55) with an 81% (25/31)
surgical mortality. A significant number of patients will have
ventricular septal rupture without early evidence of circula-
tory collapse. Onset of circulatory collapse in this situation is
unpredictable, and a superior surgical outcome is realised
when emergent surgery is performed before the onset of car-
diogenic shock. In keeping with the ACC/AHA guidelines, we
recommend urgent surgery for our patients with newly diag-
nosed ventricular septal rupture. Similarly, all patients with
mechanical mitral regurgitation and subacute rupture should
be emergently considered for surgical intervention.
FUTURE DIRECTIONS
The role of L-NMMA, a selective nitric oxide inhibitor, is
promising in this setting.
37
The utility of GIK (glucose, insulin,
and potassium) m etabolic support for cardiogenic shock
patients is an intriguing but unanswered question. However,

we recommend intensive insulin treatment to normalise blood
glucose in those with elevated values. The DIGAMI study sug-
gested that this strategy was beneficial for acute MI patients.
In a study of intensive care unit patients, those with hypergly-
caemia who were randomised to intensive insulin had reduced
mortality rates.
38
The role of selection of patients for wearable left ventricular
assist devices and their clinical utility in the setting of shock
following MI needs to be explored. Patients who are
candidates for cardiac transplantation should receive bridging
left ventricular assist devices.
CONCLUSION
Early recognition and transfer of high risk patients and adop-
tion of a primary PCI strategy may decrease the incidence of
cardiogenic shock. Establishing the aetiology of shock and
early definition of coronary anatomy in the setting of pump
failure are crucial. We recommend urgent revascularisation
supported by IABP for patients aged < 75 years in cardiogenic
shock caused by pump failure. A selective approach is
advocated for the elderly. Regional care centres that are expe-
rienced in the management of shock should be designated and
protocols developed for rapid transport of critically ill patients.
Further research is needed in the areas of pharmacologic and
mechanical haemodynamic support, refinement of revascu-
larisation strategies, and outcome modelling.
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c Classic early paper on the utility of IABP to stabilise patients in the
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EDUCATION IN HEART
*
40
SECTION II: HEART FAILURE

7 CARDIAC TRANSPLANTATION
MarioCDeng
A
s a consequence of improved management in acute coronary syndromes and improved
longevity of the population, the number of patients with heart failure is growing. The
prevalence and incidence in industrialised countries are estimated to be around 1% and
0.15% of the population, respectively.
w1
Up to 10% of people with heart failure are at an advanced
stage, amounting to 300 000 patients in the USA and 60 000 in the UK. In parallel, research
w2–5
has
led to the concept of cardiac replacement by transplantation. Following the first successful heart
transplantation in 1967 in the Groote-Schuur-Hospital, Kapstadt, South Africa,
w6
the first success-
ful US heart transplant was performed in 1968 at Stanford University. In the same year, an ad hoc
committee at Harvard University established the criteria of brain death.
w7
More than 55 000 cardiac
transplants have now been performed in more than 200 hospitals worldwide (www.ishlt.org). The
combination of good surgical success rates and the presence of a growing number of well equipped
cardiac transplant programmes has created an enormous flux of heart failure patients towards
these centres. Since the annual cardiac transplantation rate will likely remain below 4500 world-
wide, with < 3000 in the USA and < 300 in the UK, it is evident that cardiac transplantation will

continue to play only a very limited quantitative role in the treatment of the advanced heart failure
syndrome.
1
Yet, its importance will continue to reside with its role as the option of last resort for
patients with advanced heart failure, offered within centres with a complete spectrum of medical
and surgical treatment options. The aim of this review is to outline a contemporary perspective on
cardiac transplantation with respect to recipient and donor management, as well as an appropriate
organisational policy. For further background reading, excellent material is available.
w8–15
c
EMERGING TREATMENTS IN ADVANCED HEART FAILURE
There has been progress in medical treatment including angiotensin converting enzyme (ACE)
inhibitors
w16
and β blockers.
2
Surgical therapies including coronary artery bypass grafting with or
without surgical anterior ventricular endocardial restoration,
w17
mitral reconstruction in cardiomyo-
pathypatientswithseveremitralregurgitation,
w18
combined with partial left ventr iculectomy in
idiopathic dilated cardiomyopathy,
w19
and left ventricular assist device therapy
3 w20–24
are evolving.
The current status of surgical therapies for advanced heart failure has recently been reviewed in
this series.

w25
Antiarrhythmic heart failure therapy with implantable defibrillators has also
improved survival.
w26
CURRENT SURVIVAL BENEFIT WITH CARDIAC TRANSPLANTATION
The appropr iate identification of heart transplant candidates is based on the expected gain in sur-
vival and quality of life compared to all organ conserving medical and surgical treatment options
in advanced heart failure. Selection criteria have been addressed in expert consensus guidelines.
4
They are a matter of increasing controversy. The assumption of a survival benefit across the entire
spectrum of advanced heart failure may not be valid any longer because of two opposing trends.
One trend is the increasing survival with emerging organ saving treatments. The other trend is that
outcomes after cardiac transplantation have not consistently improved, due to listing of more
critically ill patients, use of so-called marginal donor hearts from an extended donor pool,
1
and the
initiation of new heart transplantation centres with an inevitable learning phase.
w27
The death rates of advanced heart failure patients on the waiting list of the United Network for
Organ Sharing (UNOS), the US organisation in charge of organ transplantation (www.unos.org),
have decreased dramatically over time, from 432.2 per 1000 patient years in 1990 to 172.4 per 1000
patient years in 1999. For patients with advanced medical urgency status (status 1A, defined as
haemodynamic instability requiring ventricular assist device implantation or high dose
intravenous inotropes) in 1999, it was 581.9 per 1000 patient years, as compared with 204.7 per
1000 patient years for medical urgency status (status 1B, defined as requirement of low dose intra-
venous inotropes) and 130.7 per 1000 patient years for regular urgency status (status 2, defined as
stable outpatient condition) registrants. In comparison to waiting list outcomes, for the 1997-98
UNOS heart transplant cohort the one year post-transplantation survival rate was 86%. Recipients
*
43

in medical urgency status 1 at the time of transplant had
slightly lower one year post-transplantation survival rates
(mean (SD) 84.8 (0.7)% v 87.5 (1.0)%) than those in status 2
at the time of transplant.
The International Society for Heart and Lung Transplanta-
tion (ISHLT) Registry (www.ishlt.org) indicates an improve-
ment of one year survival after cardiac transplantation from
74.4% between 1980-86 to 85.6% between 1996-99. It does not
provide data on waiting list mortality. Thus, the survival ben-
efit with cardiac transplantation cannot be estimated from the
ISHLT registry data.
The COCPIT (comparative outcomes and clinical profiles
in transplantation) study by the German Transplantation
Society and Eurotransplant International Foundation
(www.eurotransplant.org)
5
found in a complete national
cohortofall889adultpatientslistedforafirstheart
transplant in Germany in the year 1997 that patients with a
predicted high risk of dying from heart failure according to
the Heart Failure Survival Score (HFSS), using heart rate,
mean blood pressure, aetiology, QRS duration, serum sodium,
left ventricular ejection fraction, and peak oxygen uptake,
6
experienced not only the highest risk of dying on the waiting
list (32%, 20%, 20% for high, medium, and low risk patients,
respectively; p = 0.0003), but were the only group that had a
survival benefit from transplantation. Limitations of this
cohort study included a short observation period, and incom-
pletedataintheHFSSwhichwasinpartaresultofthefact

that the COCPIT data collection was started before the HFSS
was published.
All data currently available suggest that the survival benefit
from cardiac transplantation is greatest in those patients who
are at highest risk of dying from advanced heart failure with-
out transplantation.
IMPROVEMENT OF MANAGEMENT
COUNTERBALANCES SICKER PATIENT COHORT
Consistent with this trend, a shift toward more severely ill
patients undergoing cardiac transplantation has been ob-
served during the last 10 years.
w28
With an increasing fraction
of patients undergoing orthotopic heart transplantation after
previous cardiac surgery, intraoperative management has
become more challenging.
w29 w30
The surgical challenges have
specifically increased with an increasing fraction of patients
undergoing ventricular assist implantation as bridge to trans-
plantation.
w31 w32
Furthermore, traditional contraindications for
transplant listing are being questioned—for example, with
respect to a history of Hodgkin or non-Hodgkin lymphoma,
w33
elevated pulmonary vascular resistance requiring sophisti-
cated medical bridging,
w34
increased pretransplantation panel

reactive antibody (PRA) concentrations,
w35
and left ventricular
assist device (LVAD) use
w36 w37
—implying that advances in
transplantation management have offset the increasing sever-
ity of transplant recipients.
CURRENT INDICATIONS/CONTRAINDICATIONS
AND EVALUATION PROCEDURE
Current indication criteria are a modification of the 1993
American College of Cardiology Bethesda guidelines,
4
mainly
based on the availability of the HFSS
6
(table 7.1). Conditions
considered contraindications for cardiac transplantation,
based on evidence of reduced short term and long term
survival benefit after transplantation, are listed in table 7.2.
Patients are evaluated for transplantation after referral by a
cooperating cardiologist. At the initial evaluation, a mutual
long term working relationship between patient, relatives, and
the team is established. The evaluation includes the tests
summarised in table 7.3. The listing decision involves a
recommendation by the team and decision by the patient. The
complexity of the evaluation process mandates a team
approach. For the patient with permanent contraindications
the team offers continued care with the same intensity as for
a transplant candidate, in conjunction with the primary care

physician and cardiologist. At the time of listing, the patient
and family are informed about the peculiarities of the waiting
time, the perioperative period, the long term maintenance
medication, and the rules of living with the new heart. A flex-
ible schedule of outpatient appointments constitutes the cor-
nerstone of waiting time surveillance. Deteriorating heart
failure may precipitate organ failure. The bridging of organ
function is part of the management of heart transplant candi-
dates. If irreversible organ dysfunction ensues, the termina-
tion of life support must be considered, incorporating the
patient’s preferences. The patient must know that in case of a
donor organ offer, acceptance of the organ depends on the
judgment of donor organ quality by the donor surgical team.
EXPANSION OF DONOR CRITERIA
Donor heart acceptance criteria need to be continuously
revised in order to responsibly increase the donor pool. These
Abbreviations
COCPIT, Comparative Outcomes and Clinical Profiles In
Transplantation
CMV, cytomegalovirus
HFSS, Heart Failure Survival Score
ISHLT, International Society for Heart and Lung Transplanta-
tion
LVAD, left ventricular assist device
PRA, panel reactive antibody
REMATCH, Randomized Evaluation of Mechanical Assistance
for the Treatment of Congestive Heart failure
UNOS, United Network for Organ Sharing
Table 7.1 Cardiac transplantation indication criteria
1. Accepted

Heart Failure Survival Score (HFSS, Aaronson
1997
6
)highrisk
Peak V
O
2
<10 ml/kg/min after reaching anaerobic
threshold
NYHA class III/IV heart failure refractory to maximal
medical treatment
Severely limiting ischaemia not amenable to
interventional or surgical revascularisation
Recurrent symptomatic ventricular arrhythmias
refractory to medical, ICD, and surgical treatment
2. Probable
HFSS medium risk
Peak V
O
2
<14 ml/kg/min and severe functional
limitations
Instability of fluid status and renal function despite
good compliance, daily weights, salt and fluid
restriction and flexible diuretics
Recurrent unstable ischaemia not amenable to
revascularisation
3. Inadequate
HFSS low risk alone
Peak V

O
2
>15–18 ml/kg/min without other
indications
Left ventricular ejection fraction <20 % alone
History of NYHA class III/IV symptoms alone
History of ventricular arrhythmias alone
ICD, implantable cardioverter-defibrillator; NYHA, New York Heart
Association; V
O
2
, oxygen consumption.
EDUCATION IN HEART
*
44