Air Versus Oxygen in ST-Segment Elevation Myocardial Infarction

Running title: Stub et al.; AVOID Study

Dion Stub, MBBS, PhD1,2,3; Karen Smith, BSc, PhD4,5,6; Stephen Bernard,
MBBS, MD1,4,5; Ziad Nehme, BEmergHlth(Pmedic)4,5; Michael Stephenson,
RN, BHlthSc, Grad Dip (MICA)4,5; Janet E. Bray, RN, PhD1,5; Peter Cameron,
MBBS, MD5 ; Bill Barger, MACAP4 ; Andris H. Ellims, MBBS, PhD1,2, Andrew
J. Taylor, MBBS, PhD1,2; Ian T. Meredith, BSc, MBBS, PhD5,7; David M. Kaye,
MBBS, PhD1,2,5, on behalf of the AVOID Investigators
Downloaded from http://circ.ahajournals.org/ by guest on June 22, 2016
DOI: 10.1161/CIRCULATIONAHA.114.014494 2
Abstract
BackgroundOxygen is commonly administered to patients with STelevation myocardial infarction (STEMI) despite previous studies suggesting
a possible increase in myocardial injury due to coronary vasoconstriction
and heightened oxidative stress.
Methods and ResultsWe conducted a multicenter, prospective,
randomized, controlled trial comparing oxygen (8 L/min) with no
supplemental oxygen in patients with STEMI diagnosed on paramedic 12lead electrocardiogram. Of 638 patients randomized, 441 were confirmed
STEMI patients who underwent primary endpoint analysis. The primary
endpoint was myocardial infarct size as assessed by cardiac enzymes,
troponin (cTnI) and creatine kinase (CK). Secondary endpoints included
recurrent myocardial infarction, cardiac arrhythmia and myocardial infarct
size assessed by cardiac magnetic resonance (CMR) imaging at 6 months.
Mean peak troponin was similar in the oxygen and no oxygen groups (57.4
mcg/L vs. 48.0 mcg/L; ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.56;
P=0.18). There was a significant increase in mean peak CK in the oxygen
group compared to the no oxygen group (1948 U/L vs. 1543 U/L; means
ratio, 1.27; 95% CI, 1.04 to 1.52; P= 0.01). There was an increase in the rate
of recurrent myocardial infarction in the oxygen group compared to the no
oxygen group (5.5%vs.0.9%, P=0.006) and an increase in frequency of
cardiac arrhythmia (40.4% vs. 31.4%; P=0.05). At 6-months the oxygen
group had an increase in myocardial infarct size on CMR (n=139; 20.3
grams vs. 13.1 grams; P=0.04).
ConclusionsSupplemental oxygen therapy in patients with STEMI but
without hypoxia may increase early myocardial injury and was associated
with larger myocardial infarct size assessed at six months. Clinical Trial
Registration Informationclinicaltrials.gov. Identifier: NCT01272713.

Effects of Prior Aspirin and Anti-Ischemic Therapy

on Outcome of Patients With Unstable Angina 1
Steven Borzak MD Christopher P. Cannon MD Phillip L. Kraft MD Lori Douthat RN Richard C.
Becker MD Sebastian T. Palmeri MD Timothy Henry MD Judith S. Hochman MD Joanna
Fuchs MD Elliott M. Antman MD Carolyn McCabe BS Eugene Braunwald MD
, for the TIMI 7 Investigators
DOI: http://dx.doi.org/10.1016/S0002-9149(97)01006-0

Abstract

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References

Abstract
Both aspirin and -adrenergic blocking drugs have been shown to reduce the risk of death or acute
myocardial infarction (AMI) in patients with unstable angina, but their effect during chronic use on the
presentation of acute coronary syndromes is less well defined. Calcium antagonists and oral nitrates are
also widely prescribed for patients with coronary disease, but their effect on presentation of acute
myocardial ischemia is unknown. We retrospectively examined the effects of prior aspirin and anti-ischemic
medical therapy on clinical events in 410 patients hospitalized for unstable angina. Ischemic pain occurred
at rest for a duration of 5 to 60 minutes. During hospitalization, 97% of patients received aspirin and all
received the direct thrombin inhibitor bivalirudin for at least 72 hours. Despite being older and more likely to
have risk factors for coronary disease and poor outcome, patients receiving aspirin before admission were
less likely to present with nonQ-wave AMI (5% vs 14% in patients not on aspirin, p = 0.004). Prior
blocker, calcium antagonist, or nitrate administration did not appear to modify presentation as unstable
angina or nonQ-wave AMI. In a multivariate model, the combined incidence of death, AMI not present at
enrollment, or recurrent angina was best predicted by age (adjusted odds ratio [95% confidence interval]
2.38 [1.14 to 3.98]) and presence of electrocardiographic changes with pain on presentation (adjusted
odds ratio 2.83 [1.50 to 5.35]) but was not related to prior or in-hospital medical therapy. Thus, aspirin but
not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a
decreased incidence of nonQ-wave AMI on admission.

Int J Cardiol. 2013 Sep 30;168(2):915-21. doi: 10.1016/j.ijcard.2012.10.050. Epub 2012 Nov 17.

Early intravenous beta-blockers in patients with acute coronary

syndrome--a meta-analysis of randomized trials.
Chatterjee S1, Chaudhuri D, Vedanthan R, Fuster V, Ibanez B, Bangalore S, Mukherjee
D.
Author information
Abstract
BACKGROUND:
Intravenous (IV) beta-blockade is currently a Class IIa recommendation in early management of
patients with acute coronary syndromes (ACS) without obvious contraindications.
METHODS:
We searched the PubMed, EMBASE and the Cochrane Register for Controlled Clinical Trials for
randomized clinical trials from 1965 through December, 2011, comparing intravenous betablockers administered within 12 hours of presentation of ACS with standard medical therapy
and/or placebo. The primary outcome assessed was the risk of short-term (in-hospital mortalitywith maximum follow up duration of 90 days) all-cause mortality in the intervention group versus
the comparator group. The secondary outcomes assessed were ventricular tachyarrhythmias,
myocardial reinfarction, cardiogenic shock, and stroke. Pooled treatment effects were estimated
using relative risk with Mantel-Haenszel risk ratio, using a random-effects model.
RESULTS:
Sixteen studies enrolling 73,396 participants met the inclusion exclusion criteria. In- hospital
mortality was reduced 8% with intravenous beta-blockers, RR=0.92 (95% CI, 0.86-1.00; p=0.04)
when compared with controls. Moreover, intravenous beta-blockade reduced the risk of
ventricular tachyarrhythmias (RR=0.61; 95 % CI 0.47-0.79; p=0.0003) and myocardial
reinfarction (RR=0.73, 95 % CI 0.59-0.91; p=0.004) without increase in the risk of cardiogenic
shock, (RR=1.02; 95% CI 0.77-1.35; p=0.91) or stroke (RR=0.58; 95 % CI 0.17-1.98; p=0.38).
CONCLUSIONS:
Intravenous beta-blockers early in the course of appropriate patients with ACS appears to be
associated with significant reduction in the risk of short-term cardiovascular outcomes, including
a reduction in the risk of all-cause mortality.

Am Heart J. 2011 May;161(5):864-70. doi: 10.1016/j.ahj.2011.01.006. Epub 2011 Apr 12.

Treatment and outcomes in patients with myocardial infarction

treated with acute -blocker therapy: results from the American
College of Cardiology's NCDR().
Kontos MC1, Diercks DB, Ho PM, Wang TY, Chen AY, Roe MT.
Author information
Abstract
BACKGROUND:
Although -blockers (BBs) reduce long-term mortality in patients after myocardial infarction (MI),
data regarding acute usage are conflicting.
METHODS:
We examined acute (24 hours) BB use in 34,661 patients with ST-elevation MI (STEMI) and
non-ST-segment MI (NSTEMI) included in the NCDR() ACTION Registry()-GWTG (291
US hospitals) between January 2007 and June 2008. Patients with contraindications or did not
receive BBs or with missing data were excluded. We analyzed the use and impact of BB
stratified by variables associated with increased risk for shock specified in the recent guidelines:
age >70 years, symptoms >12 hours (STEMI patients), systolic blood pressure <120 mm Hg,
and heart rate >110 beat/min on presentation.
RESULTS:
Among patients without contraindications, at least 1 high-risk variable was found in 45% of
STEMI and 63% of NSTEMI patients. In-hospital complications including cardiogenic shock,
mortality, and the composite outcome of shock or mortality were significantly increased with
more shock risk factors in both STEMI and NSTEMI patients. Very early use in the emergency
department was associated with a significantly increased risk of shock for both STEMI and
NSTEMI patients compared to patients treated later but within 24 hours.
CONCLUSIONS:
Risk factors for shock are common in STEMI and NSTEMI patients treated with early BBs.
Increasing numbers of risk factors were associated with increased risk for shock or death in
patients treated with BBs. These results are consistent with current recommendations for
avoiding early BB treatment for patients with acute MI.

Am J Med. 2007 Aug;120(8):685-92.

Impact of acute beta-blocker therapy for patients with non-STsegment elevation myocardial infarction.
Miller CD1, Roe MT, Mulgund J, Hoekstra JW, Santos R, Pollack CV Jr, Ohman
EM, Gibler WB, Peterson ED.
Author information
Abstract
PURPOSE:
Early use of beta-blockers is a quality indicator for the treatment of patients with non-STsegment elevation myocardial infarction (NSTEMI), despite limited data from randomized clinical
trials in this population. We sought to determine the impact of acute beta-blocker therapy on
outcomes in patients with NSTEMI.
SUBJECTS AND METHODS:
We examined acute (<24 hours) beta-blocker use in 72,054 patients with NSTEMI from the Can
Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early
Implementation of the American College of Cardiology/American Heart Association Guidelines
(CRUSADE) initiative at 509 US hospitals from 2001-2004. We analyzed patient and provider
factors associated with beta-blocker use and the impact of beta-blocker therapy on unadjusted,
risk-adjusted, and propensity matched outcomes in the overall sample and among selected
high-risk subgroups.
RESULTS:
A total of 82.5% of patients without documented contraindications received acute beta-blocker
therapy. Factors strongly associated with acute beta-blocker use included prior beta-blocker
use, higher presenting systolic blood pressure, lower heart rate, lack of signs of heart failure,
and cardiology care. Acute beta-blocker use was associated with lower in-hospital mortality
(unadjusted 3.9% vs 6.9%, P <.001, adjusted odds ratio 0.66, 95% confidence interval 0.600.72), lower adjusted mortality among most of 6 subgroups determined by propensity to receive
acute beta-blockers, and lower adjusted mortality in patients with and without signs of heart
failure and in those <80 years and those > or =80 years old.
CONCLUSIONS:
The majority of NSTEMI patients receive acute beta-blocker therapy. Certain patient subgroups
remain undertreated. Because treatment with acute beta-blockers was associated with
improved clinical outcomes in nearly all patient subgroups assessed, broader use in patients
with NSTEMI appears warranted.

Circulation. 1988 Jul;78(1):1-9.

Long-term prognosis for patients with variant angina and

influential factors.
Yasue H1, Takizawa A, Nagao M, Nishida S, Horie M, Kubota J, Omote S, Takaoka
K, Okumura K.
Author information
Abstract
Two hundred forty-five patients with variant angina were followed for an average of 80.5 months
(range, 36-184 months). Survival rate at 1, 3, 5, and 10 years was 98%, 97%, 97%, and 93%,
respectively. Survival rate without myocardial infarction at 1, 3, 5, and 10 years was 86%, 85%,
83%, and 81%, respectively. By univarite analysis, ST segment elevation in both the anterior
and inferior electrocardiographic leads was the most important factor influencing survival,
followed by use of calcium antagonists, left ventricular function, smoking, and alcohol intake.
The variables that significantly correlated with survival without myocardial infarction were use of
calcium antagonists, left ventricular function, extent and severity of coronary artery disease,
coronary artery bypass surgery, and disease activity. Multivariate analysis using the Cox
proportional hazards model showed that intake of calcium antagonists, extent and severity of
coronary artery disease, and ST segment elevation in both the anterior and inferior leads were
significant independent predictors of survival without myocardial infarction. We conclude that
long-term prognosis for patients with variant angina is relatively good and that use of calcium
antagonists improves it.

Otras clases de frmacos

El diltiazem y el verapamilo tienen una eficacia similar para el alivio
de los sintomas y, en este sentido, parecen ser equivalentes a los
bloqueadores beta121,122. En la decada de los anos ochenta, un estudio
que comparaba el tratamiento con nifedipino o metoprolol en la
angina inestable se interrumpio prematuramente debido a un exceso
de reinfartos en el brazo de nifedipino, mientras que los estudios que
compararon verapamilo con placebo mostraron reducciones significativas
de muerte subita, reinfarto y mortalidad total, especialmente
en pacientes con funcion del VI conservada123,124. La ranolazina, un farmaco
que previene la sobrecarga de calcio en la isquemia, no redujo la
incidencia de MACE comparada con placebo en el estudio MERLIN,
que incluyo a 3.279 pacientes con SCASEST, pero redujo la tasa de
isquemia recurrente125. Se puede considerar la administracion de bloqueadores
de los canales del calcio y ranolazina para pacientes a los
que no se pueda revascularizar adecuadamente y que tengan isquemia
residual a pesar del tratamiento con bloqueadores beta. Se puede
emplear todos los tipos de bloqueadores de los canales del calcio en la
angina vasospastica63.

N Engl J Med. 1983 Aug 18;309(7):396-403.

Protective effects of aspirin against acute myocardial infarction

and death in men with unstable angina. Results of a Veterans
Administration Cooperative Study.
Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE
3rd, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC,Chesler
E, DeMots H.
Abstract
We conducted a multicenter, double-blind, placebo-controlled randomized trial of aspirin
treatment (324 mg in buffered solution daily) for 12 weeks in 1266 men with unstable angina
(625 taking aspirin and 641 placebo). The principal end points were death and acute myocardial
infarction diagnosed by the presence of creatine kinase MB or pathologic Q-wave changes on
electrocardiograms. The incidence of death or acute myocardial infarction was 51 per cent lower
in the aspirin group than in the placebo group: 31 patients (5.0 per cent) as compared with 65
(10.1 per cent); P = 0.0005. Nonfatal acute myocardial infarction was 51 per cent lower in the
aspirin group: 21 patients (3.4 per cent) as compared with 44 (6.9 per cent); P = 0.005. The
reduction in mortality in the aspirin group was also 51 per cent--10 patients (1.6 per cent) as
compared with 21 (3.3 per cent)--although it was not statistically significant; P = 0.054. There
was no difference in gastrointestinal symptoms or evidence of blood loss between the treatment
and control groups. Our data show that aspirin has a protective effect against acute myocardial
infarction in men with unstable angina, and they suggest a similar effect on mortality.

RANDOMISED TRIAL OF INTRAVENOUS

ATENOLOL AMONG 16 027 CASES OF
SUSPECTED ACUTE MYOCARDIAL INFARCTION:
ISIS-1
ISIS-1 (FIRST INTERNATIONAL STUDY OF INFARCT SURVIVAL)
COLLABORATIVE GROUP

Abstract
Between mid-1981 and Jan 1, 1985, 16 027 patients entering 245 coronary care
units at a mean of 50 h after the onset of suspected acute myocardial infarction
were randomised either to a control group or to a group receiving atenolol (5-10 mg
iv immediately, followed by 100 mg/day orally for 7 days). Vascular mortality during
the treatment period (days 0-7) was significantly lower (2p<004) in the treated
group, 313/8037 (389%) versus 365/7990 (457%), but this 15% difference has
wide 95% confidence limits (from about zero to about a quarter). No subgroups
were identified in which the proportional difference in days 0-7 was clearly better, or
clearly worse, than 15%. After the treatment period, there was only a slight further
divergence (691 vs 703 additional vascular deaths by Jan 1, 1985). Thus, overall
vascular. mortality was significantly lower in the atenolol group at one year (lifetable estimates: 107% atenolol vs 120% control; 2p<001) but not at Jan 1, 1985
(crude percentages: 125% vs 134%; 2p<007). However, atenolol patients were
more likely than controls to be discharged on beta-blockers, which can account for
much of the additional difference in vascular mortality after day 7. Immediate betablockade increased the extent of inotropic drug use (50% vs 34%, 2p<00001),
chiefly on days 0-1, but despite this most of the improvement in vascular mortality
was seen during days 0-1 (121 vs 171 deaths). Treatment did not appear to
decrease the number in whom cardiac enzymes rose to above twice the local upper
limit of normal. Slightly fewer non-fatal cardiac arrests (189 vs 198) and
reinfarctions (148 vs 161) were recorded in the atenolol group, neither difference
being significant. Systematic review of fatal and of non-fatal events in ISIS-1 and in
all other randomised trials of iv beta-blockade reinforces the suggestion that
treatment reduces mortality in the first week by about 15%, but with a rather less
extreme effect in days 0-1 than was observed in ISIS-1 alone. It also provides
highly significant (2p<00002) evidence of an effect on the combined end-point of

death, arrest, or reinfarction, suggesting that treatment of about 200 patients would
lead to the avoidance of 1 reinfarction, 1 arrest, and 1 death during days 0-7. ISIS-1
suggests these early gains will persist.

COMMIT
Lancet. 2005 Nov 5;366(9497):1622-32.

Early intravenous then oral metoprolol in 45,852 patients with

acute myocardial infarction: randomised placebo-controlled trial.
Chen ZM1, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, Xie JX, Liu LS; COMMIT
(ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.
Author information
Abstract
BACKGROUND:
Despite previous randomised trials of early beta-blocker therapy in the emergency treatment of
myocardial infarction (MI), uncertainty has persisted about the value of adding it to current
standard interventions (eg, aspirin and fibrinolytic therapy), and the balance of potential benefits
and hazards is still unclear in high-risk patients.
METHODS:
45,852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were
randomly allocated metoprolol (up to 15 mg intravenous then 200 mg oral daily; n=22,929) or
matching placebo (n=22,923). 93% had ST-segment elevation or bundle branch block, and 7%
had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in
hospital (mean 15 days in survivors) and 89% completed it. The two prespecified co-primary
outcomes were: (1) composite of death, reinfarction, or cardiac arrest; and (2) death from any
cause during the scheduled treatment period. Comparisons were by intention to treat, and used
the log-rank method. This study is registered with ClinicalTrials.gov, number NCT 00222573.
FINDINGS:
Neither of the co-primary outcomes was significantly reduced by allocation to metoprolol. For
death, reinfarction, or cardiac arrest, 2166 (9.4%) patients allocated metoprolol had at least one
such event compared with 2261 (9.9%) allocated placebo (odds ratio [OR] 0.96, 95% CI 0.901.01; p=0.1). For death alone, there were 1774 (7.7%) deaths in the metoprolol group versus
1797 (7.8%) in the placebo group (OR 0.99, 0.92-1.05; p=0.69). Allocation to metoprolol was
associated with five fewer people having reinfarction (464 [2.0%] metoprolol vs 568 [2.5%]
placebo; OR 0.82, 0.72-0.92; p=0.001) and five fewer having ventricular fibrillation (581 [2.5%]
vs 698 [3.0%]; OR 0.83, 0.75-0.93; p=0.001) per 1000 treated. Overall, these reductions were
counterbalanced by 11 more per 1000 developing cardiogenic shock (1141 [5.0%] vs 885
[3.9%]; OR 1.30, 1.19-1.41; p<0.00001). This excess of cardiogenic shock was mainly during

days 0-1 after admission, whereas the reductions in reinfarction and ventricular fibrillation
emerged more gradually. Consequently, the overall effect on death, reinfarction, arrest, or shock
was significantly adverse during days 0-1 and significantly beneficial thereafter. There was
substantial net hazard in haemodynamically unstable patients, and moderate net benefit in
those who were relatively stable (particularly after days 0-1).
INTERPRETATION:
The use of early beta-blocker therapy in acute MI reduces the risks of reinfarction and
ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day
or so after admission. Consequently, it might generally be prudent to consider starting betablocker therapy in hospital only when the haemodynamic condition after MI has stabilised.
Lancet. 2005 Nov 5;366(9497):1607-21.

Addition of clopidogrel to aspirin in 45,852 patients with acute

myocardial infarction: randomised placebo-controlled trial.
Chen ZM1, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; COMMIT
(ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.
Author information
Abstract
BACKGROUND:
Despite improvements in the emergency treatment of myocardial infarction (MI), early mortality
and morbidity remain high. The antiplatelet agent clopidogrel adds to the benefit of aspirin in
acute coronary syndromes without ST-segment elevation, but its effects in patients with STelevation MI were unclear.
METHODS:
45,852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were
randomly allocated clopidogrel 75 mg daily (n=22,961) or matching placebo (n=22,891) in
addition to aspirin 162 mg daily. 93% had ST-segment elevation or bundle branch block, and 7%
had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in
hospital (mean 15 days in survivors) and 93% of patients completed it. The two prespecified coprimary outcomes were: (1) the composite of death, reinfarction, or stroke; and (2) death from
any cause during the scheduled treatment period. Comparisons were by intention to treat, and
used the log-rank method. This trial is registered with ClinicalTrials.gov, number NCT00222573.

FINDINGS:
Allocation to clopidogrel produced a highly significant 9% (95% CI 3-14) proportional reduction
in death, reinfarction, or stroke (2121 [9.2%] clopidogrel vs 2310 [10.1%] placebo; p=0.002),
corresponding to nine (SE 3) fewer events per 1000 patients treated for about 2 weeks. There
was also a significant 7% (1-13) proportional reduction in any death (1726 [7.5%] vs 1845
[8.1%]; p=0.03). These effects on death, reinfarction, and stroke seemed consistent across a
wide range of patients and independent of other treatments being used. Considering all fatal,
transfused, or cerebral bleeds together, no significant excess risk was noted with clopidogrel,
either overall (134 [0.58%] vs 125 [0.55%]; p=0.59), or in patients aged older than 70 years or in
those given fibrinolytic therapy.
INTERPRETATION:
In a wide range of patients with acute MI, adding clopidogrel 75 mg daily to aspirin and other
standard treatments (such as fibrinolytic therapy) safely reduces mortality and major vascular
events in hospital, and should be considered routinely.

N Engl J Med. 2004 Apr 8;350(15):1495-504. Epub 2004 Mar 8.

Intensive versus moderate lipid lowering with statins after acute

coronary syndromes.
Cannon CP1, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal
SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection
Therapy-Thrombolysis in Myocardial Infarction 22 Investigators.
Author information
Erratum in

N Engl J Med. 2006 Feb 16;354(7):778.

Abstract
BACKGROUND:
Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal
level of low-density lipoprotein (LDL) cholesterol is unclear.
METHODS:
We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within
the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg
of atorvastatin daily (intensive therapy). The primary end point was a composite of death from
any cause, myocardial infarction, documented unstable angina requiring rehospitalization,
revascularization (performed at least 30 days after randomization), and stroke. The study was
designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect
to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24).
RESULTS:
The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol
per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in
the high-dose atorvastatin group (P<0.001). Kaplan-Meier estimates of the rates of the primary
end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the
atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin
(P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the
prespecified criterion for equivalence but did identify the superiority of the more intensive
regimen.

CONCLUSIONS:
Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering
statin regimen provides greater protection against death or major cardiovascular events than
does a standard regimen. These findings indicate that such patients benefit from early and
continued lowering of LDL cholesterol to levels substantially below current target levels.

Lancet. 1995 Mar 18;345(8951):669-85.

ISIS-4: a randomised factorial trial assessing early oral

captopril, oral mononitrate, and intravenous magnesium
sulphate in 58,050 patients with suspected acute myocardial
infarction. ISIS-4 (Fourth International Study of Infarct Survival)
Collaborative Group.
[No authors listed]
Abstract
58,050 patients entering 1086 hospitals up to 24 h (median 8 h) after the onset of suspected
acute myocardial infarction (MI) with no clear contraindications to the study treatments (in
particular, no cardiogenic shock or persistent severe hypotension) were randomised in a "2 x 2 x
2 factorial" study. The treatment comparisons were: (i) 1 month of oral captopril (6.25 mg initial
dose titrated up to 50 mg twice daily) versus matching placebo; (ii) 1 month of oral controlledrelease mononitrate (30 mg initial dose titrated up to 60 mg once daily) versus matching
placebo; and (iii) 24 h of intravenous magnesium sulphate (8 mmol initial bolus followed by 72
mmol) versus open control. There were no significant "interactions" between the effects of these
three treatments, and the results for each are based on the randomised comparison of about
29,000 active versus 29,000 control allocated patients. Captopril There was a significant 7%
(SD 3) proportional reduction in 5-week mortality (2088 [7.19%] captopril-allocated deaths vs
2231 [7.69%] placebo; 2p = 0.02), which corresponds to an absolute difference of 4.9 SD 2.2
fewer deaths per 1000 patients treated for 1 month. The absolute benefits appeared to be larger
(perhaps about 10 fewer deaths per 1000) in certain higher-risk groups, such as those
presenting with a history of previous MI or with heart failure. The survival advantage appeared
to be maintained in the longer term (5.4 [SD 2.8] fewer deaths per 1000 at 12 months). Captopril
was associated with an increase of 52 (SD 2) patients per 1000 in hypotension considered
severe enough to require termination of study treatment, of 5 (SD 2) per 1000 in reported
cardiogenic shock, and of 5 (SD 1) per 1000 in some degree of renal dysfunction. It produced
no excess of deaths on days 0-1, even among patients with low blood pressure at entry.
Mononitrate There was no significant reduction in 5-week mortality, either overall (2129 [7.34%]
mononitrate-allocated deaths vs 2190 [7.54%] placebo) or in any subgroup examined (including
those receiving short-term non-study intravenous or oral nitrates at entry). Further follow-up did
not indicate any later survival advantage. The only significant side-effect of the mononitrate
regimen studied was an increase of 15 (SD 2) per 1000 in hypotension. Those allocated active
treatment had somewhat fewer deaths on days 0-1, which is reassuring a bout the safety of
using nitrates early in acute MI.(ABSTRACT TRUNCATED AT 400 WORDS)