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Three Part Question

In [patients in the first few hours of an acute coronary syndrome] does [immediate statin therapy] lead to [reduced mortality]?

Clinical Scenario

A 55 year-old man has had twenty minutes of central chest pain. ECG shows acute anterior myocardial infarction. Having read about the so-called 'pleiotropic effects' of statins, you wonder if there is any evidence that their immediate use in acute coronary syndromes confers any mortality benefit.

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. OR AMI.mp. OR heart attack.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.mp. OR emergent.mp.] 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 ischem$).mp. OR (myocard$ ADJ ischaem$).mp. OR (heart ADJ attack).mp. OR MI.mp. OR AMI.mp.) AND (EMERGENCY-TREATMENT#.DE. OR emergent.mp. OR emergency.mp. OR immediate.mp. OR concomitant.mp. OR early.mp.) limit to human and English language
CINAHL:
(HYDROXYMETHYLGLUTARYL-COENZYME-A-REDUCTASE-INHIBITOR#.DE OR ATORVASTATIN#W..DE. OR SIMVASTATIN#W..DE. OR PRAVASTATIN#.W..DE. OR STATIN#.W..DE. OR statin$.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 ischem$).mp. OR (myocard$ ADJ ischaem$).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, 482, 116 and 143 papers were identified with the reported searches using OVID, EMBASE, CINAHL and Cochrane respectively. Only one paper, identified in OVID and EMBASE, was relevant to the three-part question.
Trials that enrolled patients who were given statins over twelve hours after symptom onset were excluded as they are not directly relevant to this three-part question. A separate review has been undertaken to identify the evidence for statin therapy within 24 hours of an acute coronary syndrome (Body, 2005).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kayikcioglu et al 1999 Turkey	72 consecutive patients admitted to a Coronary Care Unit in Turkey with acute myocardial infarction within 6 hours of symptom onset. Randomised to receive either standard therapy plus pravastatin (40mg/day) on admission (n=34) or standard therapy alone (n=35). Standard therapy consisted of thrombolysis (streptokinase or tissue plasminogen activator), aspirin 100mg od, intravenous nitroglycerine for 48 hours, intravenous heparin for 72 hours, metoprolol and ACE inhibitors.	PRCT	Incidence of ventricular late potentials	Statin group (n=34): Significant reduction in late potentials over 10 days (p=0.0063, McNemar test); Control group (n=35): Significant decrease in late potentials by day 10 (p=0.0386, McNemar test). There was no statistical analysis to directly compare the total late potential rates between the groups.	Small numbers. No power calculation. Underpowered to detect a mortality difference. No description of randomisation process. Assessment of ventricular late potentials was acknowledged to have a low reproducibility. To address this, three readings were taken five minutes apart for each measurement. However, no kappa value was reported. The statistical analyses on two of the three endpoints were uninformative.
			Ventricular arrhthmias	9 (27%) in statin group (including VF in 2) vs. 22 (63%) in control group (including VF in 5). P=0.006.
			Major adverse cardiac events in hospital (cardiac death, angina, reinfarction)	4 in statin group (0 deaths) vs 8 in control group (2 deaths). No statistical analysis

Comment(s)

The benefits of statin therapy in secondary prevention after an acute coronary syndrome is well-established. This is largely as a result of their lipid-lowering effect. However, pathophysiologic data have shown that statins have a number of additional, so-called pleiotropic, effects. These include a reduction in thrombus formation, improved endothelial function, reduction of inflammation at the site of the atherosclerotic plaque, inhibition of platelet reactivity and aggregation, reduced levels of inflammatory markers including CRP, as well as a possible stabilising effect on the fibrous cap of the atherosclerotic plaque. All of these effects would be potentially beneficial in acute coronary syndromes. Several trials have investigated the benefit of statin therapy within the first few days of an acute coronary syndrome (MIRACL, L-CAD, A To Z, PROVE-IT, FLORIDA) (Schwartz 2001; Arntz 2000; de Lemos 2004; Canon 2004; Liem 2002). However, there has been relatively little research into the potentially beneficial effects of statins used in the emergency situation. The FACS trial is currently underway in the Czech Republic and Slovakia to evaluate the efficacy of fluvastatin given on admission to 1,000 patients with acute coronary syndromes (Ostadal 2005). The results may help to confirm the value of statins in this situation. At present, the only available published research did detect a statistically significant reduction in ventricular arrhythmias with early statins, although the trial design was suboptimal and the numbers small.

Editor Comment

Another review is available on a related topic (BET 899).

Clinical Bottom Line

A beneficial effect of immediate statin therapy is physiologically plausible and is supported by the evidence from one small trial. More evidence is anticipated in the near future.

References

1. Kayikcioglu M; Can L; Evrengul H; Payzin S; Kultursay H The effect of statin therapy on ventricular late potentials in acute myocardial infarction International Journal of Cardiology 2003; 90(1): 63-72
2. Arntz H; Agrawal R; Wunderlich W; et al Beneficial effects of pravastatin (+/- cholestyramine/niacin) initiated immediately after a coronary event (The Randomized Lipid-Coronary Artery Disease (L-CAD) Study) American Journal of Cardiology 2000; 86: 1293-1298
3. Schwartz GG; Olsson AG; Ezekowitz MD; et al Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: a randomized controlled trial JAMA 2001; 285: 1711-1718
4. Liem AH; van Boven AJ; Veeger NJGM; Withagen AJ et al Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial European Heart Journal 2002; 23: 1931-1937
5. Cannon CP; Braunwald E; McCabe CH; Rader DJ; Rouleau JF; Belder R; Joyal SV; Hill KA; Pfeffer MA; Skene AM Intensive versus moderate lipid lowering with statins after acute coronary syndromes New England Journal of Medicine 2004; 350(15): 1495-1504
6. de Lemos JA; Blazing MA; Wiviott SD; Lewis EF; et al. Early versus intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial JAMA 2004; 292(11): 1307-1316
7. 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
8. Body R. Don't put off till tomorrow: Statins should be given within 24 hours of onset in acute coronary syndromes[Online] Available at:http://www.bestbets.org/cgi-bin/bets.pl?record=00899 (Accessed 22/05/05)