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Three Part Question

In [an acute coronary syndrome] does [initiation of statin therapy within 24 hours vs. later initiation] lead to [superior in-hospital and late mortality]?

Clinical Scenario

A 55 year-old man has had an anterior myocardial infarction. His symptoms started twelve hours ago. He has already been given aspirin, thrombolysis, nitrates, opiates, beta-blockers and clopidogrel. You know he ought to start statin therapy. Having read about the 'pleotropic effects' of statins, you wonder if there is any benefit in starting this therapy within the first 24 hours.

Search Strategy

OVID Medline 1966-May 2005
EMBASE 1974 - May 2005 via Dialog Datastar
CINAHL 1982 - May 2005 via Dialog Datastar
The Cochrane Library 2005, Issue 2
OVID:[exp Angina Pectoris/ OR exp Coronary Disease/ OR exp Myocardial Ischemia/ Or exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR acute coronary syndrome.mp. OR MI.mp. OR (myocard$ ADJ ischaem$).mp. OR (myocard$ ADJ ischem$).mp. OR (myocard$ ADJ infarct$).mp.] AND [exp Simvastatin/ OR exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/ OR exp Lovastatin/ OR $statin$.af.] AND [exp Time Factors/ OR acute.af. OR early.af. OR immediate.af. OR concomitant.af. OR emergency.af. OR emergent.af.] limit to human and English language
EMBASE:
(HYDROXYMETHYLGLUTARYL-COENZYME-A-REDUCTASE-INHIBITOR#.DE. OR ATORVASTATIN#.W..DE. OR SIMVASTATIN#.W..DE. OR PRAVASTATIN#.W..DE. OR STATIN#.W..DE. OR statin$.mp.) AND (HEART-INFARCTION#.DE. OR ACUTE-HEART-INFARCTION#.DE. OR HEART-MUSCLE-ISCHEMIA#.DE. OR UNSTABLE-ANGINA-PECTORIS#.DE. OR (myocard$ ADJ infarct$).mp. OR (myocard$ ADJ ischaem$).mp. OR (myocard$ ADJ ischem$).mp. OR (heart ADJ attack).mp. OR MI.mp. OR AMI.mp.) AND (EMERGENCY-TREATMENT#.DE. OR emergent.mp. OR emergency.mp. OR immediate.mp. OR concomitant.mp. OR early.mp.) limit to human and English language
CINAHL:
(HYDROXYMETHYLGLUTARYL-COENZYME-A-REDUCTASE-INHIBITOR#.DE. OR ATORVASTATIN#.W..DE. OR SIMVASTATIN#.W..DE. OR PRAVASTATIN#.W..DE. OR STATIN#.W..DE. OR statin$.mp.) AND (HEART-INFARCTION#.DE. OR ACUTE-HEART-INFARCTION#.DE. OR HEART-MUSCLE-ISCHEMIA#.DE. OR UNSTABLE-ANGINA-PECTORIS#.DE. OR (myocard$ ADJ infarct$).mp. OR (myocard$ ADJ ischaem$).mp. OR (myocard$ ADJ ischem$).mp. OR (heart ADJ attack).mp. OR MI.mp. OR AMI.mp.) AND (EMERGENCY-TREATMENT#.DE. OR emergent.mp. OR emergency.mp. OR immediate.mp. OR concomitant.mp. OR early.mp.) limit to English language
Cochrane:
((MeSH descriptor Myocardial Infarction) OR (MeSH descriptor Myocardial Ischemia) OR (MeSH descriptor Angina, Unstable)) AND (*statin*) AND (early OR emergency OR emergent OR immediate OR concomitant OR acute)

Search Outcome

Altogether 637 papers were identified using OVID Medline, of which three were relevant to the three-part question. 143 papers were identified in the Cochrane Library, one of which was relevant to the three-part question. 482 papers were identified using EMBASE, three of which were relevant to the three-part question and 116 papers were identified using CINAHL, none of which were relevant to the three-part question. The relevant papers identified in EMBASE and Cochrane had also been identified using OVID Medline.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bybee et al 2000 USA	Retrospective analysis of 66 patients identified as already taking or as having received a statin within 24 hours of admission for acute myocardial infarction, who were matched (for age, gender and prior history of coronary artery disease) 3:1 with a control group of 198 patients who did not receive a statin	Retrospective case-control study	In-hospital mortality	1.5% (statin) vs. 8.6% (no statin), p=0.051. Adjusted odds ratio 0.17 (0.02 - 1.67, p=0.13)	Retrospective Small numbers, no power calculation 44 of the 66 statin patients were already taking a statin at presentation. Therefore, the beneficial effect could have been due to either long-term statin therapy, early statin initiation or selection bias. Four different statins were used in the treatment group. Those who did not receive a statin were also less likely to receive other therapy (aspirin, p=0.17; ACE inhibitor, p=0.008; calcium channel blocker, p=0.009, beta-blocker, p=0.09; nitrates, p=0.054).
			In-hospital death or reinfarction	3.0% (statin) vs. 12.1% (no statin), p<0.05. Adjusted odds ratio 0.26 (0.06 - 1.26, p<0.09)
Thompson et al 2003 Australia	3408 patients presenting within 24 hours of onset of symptoms with acute myocardial infarction (58.9%) or unstable angina (41.1%). Randomised to receive pravastatin (20mg (42.1%) or 40mg (57.9%), study protocol changed mid-way) or placebo. Treatment started within 24 hours of symptom onset and continued for four weeks.	Multicentre PRCT	Death from any cause, reinfarction, readmission to hospital with unstable angina	11.6% (pravastatin) vs. 12.4% (placebo). Absolute risk reduction 0.8% (95% CI -1.4 - 3.0%); relative risk reduction 6.4% (95% CI -13.2% to 27.6%). P=0.48.	Initial sample size estimate of 10,000. Study was terminated early on recommendations of sponsors because of increasing difficulty in recruiting patients due to changing clinical practice and increasing rates of statin use in the population. Thus the study was underpowered to detect a difference. Dose of pravastatin was changed midway through the study Pravastatin was compared with placebo. A comparison of early (<24h) versus late (>24h) statin initiation may have been more relevant. The proportion of patients with cholesterol <5mmol/l was higher in the pravastatin group (p=0.036)
			Fatal myocardial infarction	0.5% (pravastatin) vs. 0.9% (placebo). Not significant
			Death excluding fatal MI	11.6% (pravastatin) vs. 12.4% (placebo). Not significant
			Serious adverse events	No significant differences. Persistently abnormal liver function tests in 1.5% (pravastatin) vs. 1.1% (placebo), not significant)
Saab et al 2004 USA	1,639 consecutive patients, who had been admitted with a diagnosis of unstable angina or acute myocardial infarction, were eligible for inclusion. 1,284 had received statins within 24 hours of presentation; 355 patients received statins over 24 hours after presentation (according to the discretion of the physicians. The study was retrospective).	Retrospective prognostic cohort	Death/reinfarction/stroke (in-hospital)	7.01% (<24h) vs. 10.43% (>24h), p=0.033	Retrospective, thus unblinded with no placebo control and subject to selection bias. Unmatched baseline characteristics (early treatment group was younger (p=0.016), reported previous myocardial infarction or coronary bypas more frequently and had more hyerlipidaemia (all p<0.01)), although adjustments were made to account for these differences in the statistical analysis. No data on which statins were taken and doses
			Cardiac arrest (in-hospital)	1.71% (<24h) vs. 5.07% (>24h), p<0.01. Odds ratio 0.45 (95% CI 0.22-0.95)
			Pulmonary oedema (in-hospital)	6.93% (<24h) vs. 15.77% (>24h), p<0.01 (odds ratio 0.44, 95% CI 0.28-0.69)
			Cardiogenic shock (in-hospital)	2.18% (<24h) vs. 7.32% (>24h), p<0.01 (odds ratio 0.30, 95% CI 0.15-0.58)
			Death/reinfarction/stroke (6 months)	32.75% (<24h) vs. 38.26% (>24h), p=0.091

Comment(s)

The benefits of statin therapy for primary and secondary prevention of acute coronary syndromes are well established. There is now evidence that statins not only reduce LDL cholesterol but also exert so-called pleiotropic effects, potentially improving endothelial function and stabilising vulnerable atherosclerotic plaques. If this is so, the benefits of statin therapy would be expected to be maximal when given early after the onset of an acute coronary syndrome, when the risk of complications or recurrence is at its highest. Although the trials that have been done are either retrospective or underpowered to detect a difference in outcome, they all showed a trend towards reduced mortality when statins are given early. Saab et al noted a significant reduction in the combined endpoint of in-hospital death/reinfarction/stroke. Bybee et al also showed a significantly lower in-hospital mortality in the early statin group, although the difference was not significant following adjustment for confounding factors. Thompson et al demonstrated no significant difference in outcome, although there was a trend towards reduced death/reinfarction/readmission in those given pravastatin 40mg. No increase in adverse effects was reported with early statins in any of the studies. In the light of growing evidence, both clinical and pathophysiological, it would seem that statins are best given early in an acute coronary syndrome. The result of the forthcoming FACS trial may provide more evidence in the near future (Ostadal 2005).

Editor Comment

Another BET is available on a closely related topic (BET 898).

Clinical Bottom Line

Statins should be given as soon as possible in acute coronary syndromes

References

1. Bybee KA; Wright RS; Williams BA; Murphy JG; Homes DR Jr; Kopecky SL Effect of concomitant or very early statin administration on in-hospital mortality and reinfarction in patients with acute myocardial infarction American Journal of Cardiology 2001; 87(6): 771-4
2. Thompson PL; Meredith I; Amerena J; Campbell TJ; Sloman JG; Harris P for the Pravastatin in Acute Coronary Treatment (PACT) Investigators Effect of pravastatin compared with placebo initiated within 24 hours of onset of acute myocardial infarction or unstable angina: The Pravastatin in Acute Coronary Treatment (PACT) trial American Heart Journal 2004; 148: e2
3. Saab FA; Eagle KA; Kline-Rogers E; Fang J; Otten R; Mukherjee D Comparison of outcomes in acute coronary syndrome in patients receiving statins within 24 hours of onset versus at later times American Journal of Cardiology 2004; 94: 1166-1168
4. Ostadal P; Alan D; Hajek P; Vejvoda J et al Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial) Current Controlled Trials in Cardiovascular Medicine 2005; 6: 4