Abstract

Aims

The effect of statin treatment on ventricular arrhythmic complications is uncertain. We sought to test whether statins reduce the risk of ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death.

Methods and results

We searched MEDLINE, EMBASE, and CENTRAL up to October 2010. Randomized controlled trials comparing statin with no statin or comparing intensive vs. standard dose statin, with more than 100 participants and at least 6-month follow-up were considered for inclusion and relevant unpublished data obtained from the investigators. Twenty-nine trials of statin vs. control (113 568 participants) were included in the main analyses. In these trials, statin therapy did not significantly reduce the risk of ventricular tachyarrhythmia [212 vs. 209; odds ratio (OR) = 1.02, 95% confidence interval (CI) 0.84–1.25, P = 0.87] or of cardiac arrest (82 vs. 78; OR = 1.05, 95% CI 0.76–1.45, P = 0.84), but was associated with a significant 10% reduction in sudden cardiac death (1131 vs. 1252; OR = 0.90; 95% CI 0.82–0.97, P = 0.01). This compared with a 22% reduction in the risk of other ‘non-sudden’ (mostly atherosclerotic) cardiac deaths (1235 vs. 1553; OR = 0.78, 95% CI 0.71–0.87, P < 0.001). Results were not materially altered by inclusion of eight trials (involving 41 452 participants) of intensive vs. standard dose statin regimens.

Conclusion

Statins have a modest beneficial effect on sudden cardiac death. However, previous suggestions of a substantial protective effect on ventricular arrhythmic events could not be supported.

See page 1551 for the editorial comment on this article (doi:10.1093/eurheartj/ehs027)

Introduction

About half of all deaths due to heart disease manifest as sudden cardiac arrest or sudden cardiac death, many of which occur out of hospital before acute medical help can be reached.1 While acute coronary events are the major underlying cause of sudden cardiac death, many of these are thought to be primarily caused by ventricular tachyarrhythmia.2–4 Despite the clear public health relevance of fatal arrhythmic events, strategies for their prediction and prevention remain challenging.5

During recent years, a number of observational studies have suggested that raised inflammatory markers are associated with a higher future risk of ventricular tachyarrhythmia and sudden cardiac death in a variety of clinical settings.6–9 This, together with evidence indicating that statins reduce inflammation10 as well as experimental findings on other biological effects of statins unrelated to their LDL-cholesterol-lowering effects, has raised the hope that such treatment may, in addition to its undisputed anti-atherosclerotic effects, have some direct anti-arrhythmic effects.11–13 Potential pathophysiological mechanisms for such an effect may include plaque stabilisation, changes to the transmembrane ion channel conduction, anti-oxidant and anti-proliferative effects, and decrease in the parasympathetic tone.12 Supportive evidence for such an anti-arrhythmic effect of statins comes from a number of non-randomized studies14–17 and meta-analysis of such studies,18 showing an association between statin use and reduced risk of ventricular arrhythmic events. However, reliable evidence from randomized clinical trials is not available, partly because many large-scale statin trials have not published information on such events or were not individually sufficiently powered to test this hypothesis.5

To reach a more precise estimate of effects, we set out to perform a meta-analysis of all large-scale trials of a statin vs. a control, or of a more vs. a less intensive statin regimen, which have collected, but not necessarily published, data on ventricular arrhythmic events. In particular, we sought to estimate the effects separately on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death.

Methods

Search strategy for identification of relevant studies

Study methods have been published previously.19 In brief, we searched MEDLINE (January 1966 to October 2010), EMBASE (January 1985 to October 2010), and the Cochrane Central Register of Controlled Trials (up to October 2010) for articles with a subject term ‘hydroxymethylglutaryl-coenzyme A reductase inhibitor’ or any of the following terms: ‘hydroxymethylglutaryl-co a reductase inhibitor’, ‘statin’, ‘fluvastatin’, ‘pravastatin’, ‘lovastatin’, ‘simvastatin’, ‘atorvastatin’, or ‘rosuvastatin’. The search was limited to randomized controlled trials with no language restrictions.

Review methods and selection criteria

Two reviewers independently screened all titles and abstracts for randomized controlled trials with either a parallel or factorial design, with at least one comparison of a statin vs. a control regimen or a more vs. less intensive statin regimen, and with 100 or more participants followed for at least 6 months. All such trials were considered potentially eligible; there were no restrictions placed on participant characteristics or study outcomes. We also hand-searched the reference lists of these studies to ensure that other relevant articles, such as meta-analyses of statin trials or other types of articles related to statins and cardiac arrhythmias, were not missed. After removing duplicate reports, full-text articles of all remaining reports were examined.

Data abstraction

An electronic data abstraction form was used to capture the following information: study name or investigator's name; recruitment period; mean follow-up duration; year of publication of the primary findings; randomized treatment comparisons; summary information about the studied population (number of participants, mean age, number of men, and prevalence of myocardial infarction or heart failure at randomization); the primary outcome of the study; the mean LDL-cholesterol level at randomization and at 1-year follow-up (or end of the study if follow-up duration was less than a year) by treatment allocation; and the number of patients with any of the following events: ventricular tachycardia or fibrillation (i.e. ventricular tachyarrhythmia), resuscitated cardiac arrest, sudden cardiac death, and all cardiac death. In trials where such events had not previously been reported, we asked the investigators to abstract the relevant numbers from their routine records of adverse events. We also asked the investigators to provide information about the definition used for the outcomes of interest. However, since most of these outcomes had not been pre-specified or adjudicated, no unique definition could be provided. Non-responders were sent at least one reminder after about three weeks.

Assessment of risk of bias

To identify potential sources of bias in the reported events, we considered the following domains for each trial individually: (i) selection bias (random sequence generation and allocation concealment); (ii) performance bias (blinding of participants and study investigators for the outcomes of interest); (iii) detection bias (blinding of outcome assessors); (iv) attrition bias (incomplete outcome data); (v) reporting bias (selective outcome reporting). Risk of bias for each domain was categorized into low, unclear or high. This information was used to make judgements about the overall risk of bias for each study. We followed the Cochrane Collaboration's recommendation to make judgements based on whether the ranking of the level of bias across domains could have led to any material bias on the outcomes of interests and, if it could, what the direction of the bias would likely be.20

Statistical analysis

To test the primary hypothesis that statins might reduce the risk of particular arrhythmic events, the main analyses were restricted to the trials of a statin vs. a control regimen (i.e. placebo or usual care). However, since the anti-inflammatory effect of statins—one of the key mechanisms for their potential anti-arrhythmic effects—have been suggested to be more pronounced in high-dose statin therapy,21 secondary analyses based on additional trials that had compared a more intensive vs. a standard statin regimen were also performed.

For each trial, the ‘observed minus expected’ statistic (oe) and its variance (v) were calculated from the number of patients who developed each arrhythmic event and the total number of patients in each treatment group. These (oe) values, one from every trial, were summed to produce a grand total (G), with variance (V) equal to the sum of their separate variances. The value exp(G/V) is Peto's ‘one-step’ estimate of the odds ratio (OR) and its continuity corrected 95% confidence interval (CI) is given by exp(G/V ± [0.5/V + 1.96/√V]).22 Heterogeneity between the individual trials was assessed by calculating SG2/V, where S is the sum of [oe]2/v for each trial, and testing this statistic against a χ2 distribution with degrees of freedom equal to one less than the number of trials. Tests for trend in the magnitude of the log OR when trials were ordered by their statistic size (i.e. v) were also performed.

To test whether there was a differential effect of statins on sudden cardiac death compared with other ‘non-sudden’ cardiac death, we estimated the effects on each separately (in the trials in which both outcomes were reported), comparing the two estimates using a standard χ2 test on 1 degree of freedom.

The difference in LDL cholesterol achieved between randomized groups in the trials of a more intensive vs. a standard dose statin regimen was typically much lower than that achieved in the trials of statin vs. control. If the magnitude of any true relative risk reduction was related to this difference, a standard meta-analysis of the results in the different trials could be misleading. Therefore, in addition to the main analyses, supplementary ‘LDL-weighted’ analyses were also performed to provide the estimate of the OR per 1.0 mmol/L reduction in LDL cholesterol.

Results

Figure 1 summarizes the search retrieval process. Out of 4034 abstracts reviewed, 219 papers describing 102 trials were retrieved for further examination, of which 83 met the inclusion criteria. Of these, 37 trials were included in the analysis (most of the others reported that such events were not recorded in the trial). Twenty-nine trials (including 113 568 randomized participants and ∼445 000 person-years of follow-up) compared statin vs. control23–51 and eight trials (including 41 452 randomized participants and ∼192 000 person-years of follow-up) compared more vs. less intensive LDL lowering with statins (Table 1).52–59 Twelve of the included trials had not published information on ventricular arrhythmic events previously (eight trials of statin vs. control 35,37,38,41,43,47,50,51 and five trials of more vs. less intensive statin therapy),53,55,56,58,59 and for another seven of the included trials, information from the published literature was complemented by additional unpublished data obtained from the investigators (six statin vs. control 30,31,36,39,40,42 and one more intensive vs. standard dose statin trials).54 One study was available only as a conference proceeding.45 The average achieved 1-year difference in mean LDL cholesterol between randomized treatment arms was 1.13 mmol/L for the trials of statin vs. control and 0.53 mmol/L for the trials that compared a high dose of a statin with a standard dose. The risk of bias was judged to be unclear for two trials and low for all other trials (Table 2).

Table 1

Summary of trials' characteristics

Study Year of publication of main results Mean follow-up (years) Country/region Treatment comparison
 
LDL-c differencea (mmol/L) Population characteristics
 
    Intervention Control regimen  Main inclusion criteria Total number of participants Mean age (years) Male (%) Prior MI (%) 
Statin vs. control regimen 
 PMSG-CR23 1993 0.5 Multinational P 20–40 mg Placebo 1.22 MI, angina or other risk factors 1062 55 77 34 
 4S24 1994 5.2 Nordics S 40 mg Placebo 1.77 MI or angina 4444 58 81 79 
 MAAS25 1994 4.0 Europe S 20 mg Placebo 1.40 Confirmed CHD plus other risk factors 381 56 88 55 
 PLAC-126 1995 2.3 USA P 40 mg Placebo 1.22 Confirmed CHD 408 57 78 44 
 PREDICT27 1997 0.5 France A 10 mg Placebo 1.03 Post PCI 695 58 83 37 
 AFCAPS/TexCAPS28 1998 5.3 USA L 20–40 mg Placebo 0.94 Primary prevention 6605 58 85 
 LIPID29 1998 5.6 Australia, New Zealand P 40 mg Placebo 1.03 History of MI or UA 9014 62 83 64 
 GISSI-P30 2000 1.9 Italy P 20–40 mg No treatment 0.35 Recent MI 4271 60 86 100 
 HPS31 2002 5.0 UK S 40 mg Placebo 1.29 Vascular disease or diabetes 20 536 64 75 41 
 LIPS32 2002 3.1 Europe, Canada, Brazil F 80 mg Placebo 0.92 Post PCI 1677 60 84 44 
 FLORIDA33 2002 1.0 USA F 40 mg Placebo 1.20 MI 540 61 83 100 
 ASCOT-LLA34 2003 3.2 Nordics and UK A 10 mg Placebo 1.07 Hypertension plus other risk factor 10 305 65 81 
 ALERT35 2003 5.1 Multinational F 40 mg Placebo 0.84 Renal transplant recipients 2102 50 66 34 
 CARDS36 2004 3.9 UK, Ireland A 10 mg Placebo 1.14 Type 2 diabetes plus other risk factor 2838 62 68 
 PREVEND IT37 2004 3.8 Netherlands P 40 mg Placebo 1.00 Microalbuminuric patients 864 51 65 
 ALLIANCE38 2004 4.3 USA A 10–80 mg Usual care 1.16 CHD 2442 61 82 58 
 PCAB39 2005 4.5 Japan P 10–20 mg Usual care 0.49 After CABG 335 59 85 62 
 4D40 2005 3.9 Germany A 20 mg Placebo 0.89 Diabetic haemodialysis patients 1255 66 54 18 
 NEDIAT41 2005 2.9 Sweden A 10 mg Placebo 0.71 CKD Stages 4 and 5 143 70 69 24 
 MEGA42 2006 5.3 Japan P 10–20 mg No treatment 0.67 Primary prevention 7832 58 30 
 ASPEN43 2006 4.3 Multinational A 10 mg Placebo 0.99 Type 2 diabetes 1864 61 66 17 
 SPARCL44 2006 4.9 Multinational A 80 mg Placebo 1.43 Stroke or TIA, no CHD 4731 63 60 
 CLARIDI45 2006 1.0 Belgium, Greece A 80 mg Placebo 1.68 CHD with internal cardioverter defibrillator 106 67 94 87 
 CORONA46 2007 2.7 Multinational R 10 mg Placebo 1.61 Ischemic heart failure 5011 73 76 60 
 JUPITER47 2008 1.9 Multinational R 20 mg Placebo 1.09 Primary prevention 17 802 66 62 
 GISSI-HF48 2008 3.9 Italy R 10 mg Placebo 0.92 CHF 4574 68 77 32 
 Vrtovec et al.49 2008 1.0 Slovenia A 10 mg Usual care 1.91 CHF 110 63 61 59 
 METEOR50 2009 2.0 Multinational R 40 mg Placebo 1.79 Primary prevention 981 60 57 60 
 LEADe51 2010 1.5 Multinational A 80 mg Placebo 0.30 Mild-to-moderate probable Alzheimer disease 640 74 48 
More vs. less intensive statin therapy 
 A-Z52 2004 2.0 Multinational S 80 mg S 20 mg 0.30 Acute coronary syndrome 4497 61 75 17 
 REVERSAL53 2004 1.5 USA A 80 mg P 40 mg 0.97 >20% stenosis on routine coronary angiogram 657 56 72 
 PROVE IT54 2004 2.0 Multinational A 80 mg P 40 mg 0.65 Acute coronary syndrome 4162 58 78 18 
 TNT55 2005 4.9 Multinational A 80 mg A 10 mg 0.62 Clinically evident CHD 10 001 61 81 58 
 IDEAL56 2005 4.8 Nordics, Netherlands, Iceland A 80 mg S 20 mg 0.55 MI 8888 62 81 100 
 SAGE57 2007 1.0 Multinational A 80 mg P 40 mg 0.78 Elderly with CHD and evidence of ischaemia 893 72 69 46 
 Colivicchi et al.58 2010 0.7 Italy A 80 mg A 20–40 mg 0.80 Acute presentation of severe CHD 290 75 49 100 
 SEARCH59 2010 6.7 UK S 80 mg S 20 mg 0.39 Previous MI 12 064 64 83 100 
Study Year of publication of main results Mean follow-up (years) Country/region Treatment comparison
 
LDL-c differencea (mmol/L) Population characteristics
 
    Intervention Control regimen  Main inclusion criteria Total number of participants Mean age (years) Male (%) Prior MI (%) 
Statin vs. control regimen 
 PMSG-CR23 1993 0.5 Multinational P 20–40 mg Placebo 1.22 MI, angina or other risk factors 1062 55 77 34 
 4S24 1994 5.2 Nordics S 40 mg Placebo 1.77 MI or angina 4444 58 81 79 
 MAAS25 1994 4.0 Europe S 20 mg Placebo 1.40 Confirmed CHD plus other risk factors 381 56 88 55 
 PLAC-126 1995 2.3 USA P 40 mg Placebo 1.22 Confirmed CHD 408 57 78 44 
 PREDICT27 1997 0.5 France A 10 mg Placebo 1.03 Post PCI 695 58 83 37 
 AFCAPS/TexCAPS28 1998 5.3 USA L 20–40 mg Placebo 0.94 Primary prevention 6605 58 85 
 LIPID29 1998 5.6 Australia, New Zealand P 40 mg Placebo 1.03 History of MI or UA 9014 62 83 64 
 GISSI-P30 2000 1.9 Italy P 20–40 mg No treatment 0.35 Recent MI 4271 60 86 100 
 HPS31 2002 5.0 UK S 40 mg Placebo 1.29 Vascular disease or diabetes 20 536 64 75 41 
 LIPS32 2002 3.1 Europe, Canada, Brazil F 80 mg Placebo 0.92 Post PCI 1677 60 84 44 
 FLORIDA33 2002 1.0 USA F 40 mg Placebo 1.20 MI 540 61 83 100 
 ASCOT-LLA34 2003 3.2 Nordics and UK A 10 mg Placebo 1.07 Hypertension plus other risk factor 10 305 65 81 
 ALERT35 2003 5.1 Multinational F 40 mg Placebo 0.84 Renal transplant recipients 2102 50 66 34 
 CARDS36 2004 3.9 UK, Ireland A 10 mg Placebo 1.14 Type 2 diabetes plus other risk factor 2838 62 68 
 PREVEND IT37 2004 3.8 Netherlands P 40 mg Placebo 1.00 Microalbuminuric patients 864 51 65 
 ALLIANCE38 2004 4.3 USA A 10–80 mg Usual care 1.16 CHD 2442 61 82 58 
 PCAB39 2005 4.5 Japan P 10–20 mg Usual care 0.49 After CABG 335 59 85 62 
 4D40 2005 3.9 Germany A 20 mg Placebo 0.89 Diabetic haemodialysis patients 1255 66 54 18 
 NEDIAT41 2005 2.9 Sweden A 10 mg Placebo 0.71 CKD Stages 4 and 5 143 70 69 24 
 MEGA42 2006 5.3 Japan P 10–20 mg No treatment 0.67 Primary prevention 7832 58 30 
 ASPEN43 2006 4.3 Multinational A 10 mg Placebo 0.99 Type 2 diabetes 1864 61 66 17 
 SPARCL44 2006 4.9 Multinational A 80 mg Placebo 1.43 Stroke or TIA, no CHD 4731 63 60 
 CLARIDI45 2006 1.0 Belgium, Greece A 80 mg Placebo 1.68 CHD with internal cardioverter defibrillator 106 67 94 87 
 CORONA46 2007 2.7 Multinational R 10 mg Placebo 1.61 Ischemic heart failure 5011 73 76 60 
 JUPITER47 2008 1.9 Multinational R 20 mg Placebo 1.09 Primary prevention 17 802 66 62 
 GISSI-HF48 2008 3.9 Italy R 10 mg Placebo 0.92 CHF 4574 68 77 32 
 Vrtovec et al.49 2008 1.0 Slovenia A 10 mg Usual care 1.91 CHF 110 63 61 59 
 METEOR50 2009 2.0 Multinational R 40 mg Placebo 1.79 Primary prevention 981 60 57 60 
 LEADe51 2010 1.5 Multinational A 80 mg Placebo 0.30 Mild-to-moderate probable Alzheimer disease 640 74 48 
More vs. less intensive statin therapy 
 A-Z52 2004 2.0 Multinational S 80 mg S 20 mg 0.30 Acute coronary syndrome 4497 61 75 17 
 REVERSAL53 2004 1.5 USA A 80 mg P 40 mg 0.97 >20% stenosis on routine coronary angiogram 657 56 72 
 PROVE IT54 2004 2.0 Multinational A 80 mg P 40 mg 0.65 Acute coronary syndrome 4162 58 78 18 
 TNT55 2005 4.9 Multinational A 80 mg A 10 mg 0.62 Clinically evident CHD 10 001 61 81 58 
 IDEAL56 2005 4.8 Nordics, Netherlands, Iceland A 80 mg S 20 mg 0.55 MI 8888 62 81 100 
 SAGE57 2007 1.0 Multinational A 80 mg P 40 mg 0.78 Elderly with CHD and evidence of ischaemia 893 72 69 46 
 Colivicchi et al.58 2010 0.7 Italy A 80 mg A 20–40 mg 0.80 Acute presentation of severe CHD 290 75 49 100 
 SEARCH59 2010 6.7 UK S 80 mg S 20 mg 0.39 Previous MI 12 064 64 83 100 

MI, myocardial infarction; CHD, coronary heart disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; CKD, chronic kidney disease; TIA, transient ischaemic attack; CHF, chronic heart failure; SCD, sudden cardiac death; CA, cardiac arrest; VA, ventricular arrhythmia; UA, unstable angina; A, atorvastatin; L, lovastatin; P, pravastatin; R, rosuvastatin; S, simvastatin.

aLDL-cholesterol differences are based on average differences between the two groups at 1 year (or the closest time to 1 year if 1 year data unavailable).

Table 2

Risk of bias for reported events of sudden death, cardiac arrest, and ventricular tachyarrhythmia

 Outcome available in the published literature
 
Selection bias Performance bias Detection bias Attrition bias
 
Intention-to-treat analysis Reporting bias Overall risk of bias 
 SCD CA VT    Description of withdrawals and losses to follow-up Overall risk of attrition bias    
Statin vs. control regimen 
 PMSG-CR23 Yes — — Unclear Low Low Yes Low Yes Low Low 
 4S24 Yes Yes — Unclear Low Low Yes Low Yes Low Low 
 MAAS25 Yes — — Low Low Low No Low Yes Low Low 
 PLAC-126 Yes Yes — Unclear Low Low Yes Low Yes Low Low 
 PREDICT27 Yes — — Low Low Low Yes Low Yes Low Low 
 AFCAPS/TexCAPS28 Yes — — Low Low Low Yes Low Yes Low Low 
 LIPID29 Yes — — Low Low Low Yes Low Yes Low Low 
 GISSI-P30 Yes — No Unclear Low Low Yes Low Yes Low Low 
 HPS31 Yes No No Low Low Low Yes Low Yes Low Low 
 LIPS32 Yes — — Low Low Low Yes Low Yes Low Low 
 FLORIDA33 Yes — — Unclear Low Low Yes Low Yes Low Low 
 ASCOT-LLA34 — — Yes Low Low Low Yes Low Yes Low Low 
 ALERT35 No — — Low Low Low Yes Low Yes Low Low 
 CARDS36 Yes — — Low Low Low Yes Low Yes Low Low 
 PREVEND IT37 No — — Low Low Low No Low Yes Low Low 
 ALLIANCE38 No Yes No Unclear Low Low Yes Low Yes Low Low 
 PCAB39 Yes — No Low Low Low Yes Low Yes Low Low 
 4D40 Yes — No Low Low Low Yes Low Yes Low Low 
 NEDIAT41 No — — Low Low Low Yes Low Yes Low Low 
 MEGA42 Yes — No Low Low Low Yes Low Yes Low Low 
 ASPEN43 No No No Low Low Low Yes Low Yes Low Low 
 SPARCL44 — Yes — Low Low Low Yes Low Yes Low Low 
 CLARIDI45 — — Yes Unclear Low Low No Low Yes Low Unclear 
 CORONA46 Yes Yes Yes Low Low Low Yes Low Yes Low Low 
 JUPITER47 No — — Low Low Low Yes Low Yes Low Low 
 GISSI-HF48 Yes — Yes Low Low Low Yes Low Yes Low Low 
 Vrtovec et al.49 Yes — — Unclear Low Low No Unclear Yes Low Unclear 
 METEOR50 — — No Low Low Low Yes Low Yes Low Low 
 LEADe51 Yes — No Low Low Low Yes Low Yes Low Low 

 
More vs. less intensive statin therapy 
 A-Z52 Yes — — Low Low Low Yes Low Yes Low Low 
 REVERSAL53 — No No Low Low Low Yes Low Yes Low Low 
 PROVE IT54 Yes No No Low Low Low Yes Low Yes Low Low 
 TNT55 No Yes No Unclear Low Low Yes Low Yes Low Low 
 IDEAL56 No Yes No Low Low Low Yes Low Yes Low Low 
 SAGE 57 — Yes — Low Low Low Yes Low Yes Low Low 
 Colivicchi et al.58 No — — Unclear Low Low Yes Low Yes Low Low 
 SEARCH59 — — No Low Low Low Yes Low Yes Low Low 
 Outcome available in the published literature
 
Selection bias Performance bias Detection bias Attrition bias
 
Intention-to-treat analysis Reporting bias Overall risk of bias 
 SCD CA VT    Description of withdrawals and losses to follow-up Overall risk of attrition bias    
Statin vs. control regimen 
 PMSG-CR23 Yes — — Unclear Low Low Yes Low Yes Low Low 
 4S24 Yes Yes — Unclear Low Low Yes Low Yes Low Low 
 MAAS25 Yes — — Low Low Low No Low Yes Low Low 
 PLAC-126 Yes Yes — Unclear Low Low Yes Low Yes Low Low 
 PREDICT27 Yes — — Low Low Low Yes Low Yes Low Low 
 AFCAPS/TexCAPS28 Yes — — Low Low Low Yes Low Yes Low Low 
 LIPID29 Yes — — Low Low Low Yes Low Yes Low Low 
 GISSI-P30 Yes — No Unclear Low Low Yes Low Yes Low Low 
 HPS31 Yes No No Low Low Low Yes Low Yes Low Low 
 LIPS32 Yes — — Low Low Low Yes Low Yes Low Low 
 FLORIDA33 Yes — — Unclear Low Low Yes Low Yes Low Low 
 ASCOT-LLA34 — — Yes Low Low Low Yes Low Yes Low Low 
 ALERT35 No — — Low Low Low Yes Low Yes Low Low 
 CARDS36 Yes — — Low Low Low Yes Low Yes Low Low 
 PREVEND IT37 No — — Low Low Low No Low Yes Low Low 
 ALLIANCE38 No Yes No Unclear Low Low Yes Low Yes Low Low 
 PCAB39 Yes — No Low Low Low Yes Low Yes Low Low 
 4D40 Yes — No Low Low Low Yes Low Yes Low Low 
 NEDIAT41 No — — Low Low Low Yes Low Yes Low Low 
 MEGA42 Yes — No Low Low Low Yes Low Yes Low Low 
 ASPEN43 No No No Low Low Low Yes Low Yes Low Low 
 SPARCL44 — Yes — Low Low Low Yes Low Yes Low Low 
 CLARIDI45 — — Yes Unclear Low Low No Low Yes Low Unclear 
 CORONA46 Yes Yes Yes Low Low Low Yes Low Yes Low Low 
 JUPITER47 No — — Low Low Low Yes Low Yes Low Low 
 GISSI-HF48 Yes — Yes Low Low Low Yes Low Yes Low Low 
 Vrtovec et al.49 Yes — — Unclear Low Low No Unclear Yes Low Unclear 
 METEOR50 — — No Low Low Low Yes Low Yes Low Low 
 LEADe51 Yes — No Low Low Low Yes Low Yes Low Low 

 
More vs. less intensive statin therapy 
 A-Z52 Yes — — Low Low Low Yes Low Yes Low Low 
 REVERSAL53 — No No Low Low Low Yes Low Yes Low Low 
 PROVE IT54 Yes No No Low Low Low Yes Low Yes Low Low 
 TNT55 No Yes No Unclear Low Low Yes Low Yes Low Low 
 IDEAL56 No Yes No Low Low Low Yes Low Yes Low Low 
 SAGE 57 — Yes — Low Low Low Yes Low Yes Low Low 
 Colivicchi et al.58 No — — Unclear Low Low Yes Low Yes Low Low 
 SEARCH59 — — No Low Low Low Yes Low Yes Low Low 

Selection bias is based on random sequence generation and allocation concealment; performance bias includes blinding of participants and study investigators for the outcomes of interest; detection bias includes blinding of outcome assessors; attrition bias includes the possibility of incomplete outcome data; and reporting bias includes the possibility of selective outcome reporting. Selection bias is a feature of the trial design. Performance and detection bias are overall low, given that most data were collected without any prior knowledge of the investigators of the tested hypothesis in this study at the time of event collection. All analyses in this report are based on intention-to-treat and we further mitigated the possible effect of any attrition bias and reporting bias at individual trial level by collection of additional unpublished data. SCD, sudden cardiac death; CA, cardiac arrest; VT, ventricular tachyarrhythmia.

Figure 1

Flow diagram of search retrieval process.

Figure 1

Flow diagram of search retrieval process.

Ventricular tachyarrhythmia

Only two trials had previously published information on ventricular tachyarrhythmia34,46 with another two having presented such findings at a scientific meeting.45,48 Unpublished information on ventricular tachyarrhythmia was provided from investigators for an additional 14 trials.30,31,38–40,42,43,50,51,53–56,59 Overall, these 18 trials reported 672 patients with at least one episode of ventricular tachyarrhythmia. In the primary analysis of 13 statin vs. control trials, statin therapy did not reduce the risk of ventricular tachyarrhythmia significantly (212 vs. 209; OR = 1.02, 95% CI 0.84–1.25, P = 0.87; Figure 2). This result was not materially affected when all trials were considered together (OR = 1.06; 95% CI 0.91–1.24; P = 0.48; Figure 2). There was no significant heterogeneity within the trials of statin vs. control (and no good evidence of heterogeneity within the trials of more vs. less intensive therapy), no evidence of trend according to the study size, and no evidence that the effect sizes differed significantly between the two types of trials.

Figure 2

Effect of statin therapy on ventricular tachyarrhythmia.

Figure 2

Effect of statin therapy on ventricular tachyarrhythmia.

Cardiac arrest

Twelve trials reported a total of 254 cardiac arrests24,26,31,38,43,44,46,53–57 (eight of these trials had previously published such information).24,26,38,44,46,55–57 In the seven statin vs. control trials for which cardiac arrest data were available, statin therapy did not reduce the risk of cardiac arrest significantly (82 statin vs. 78 control, OR = 1.05; 95% CI 0.76–1.45; P = 0.84; Figure 3), although the CI was wide due to the relatively few numbers of events. Including the additional five trials of intensive vs. standard dose had little effect on the estimated effect size (overall OR = 0.98; 95% CI 0.76–1.27; P = 0.92; Figure 3). There was no evidence that the effect sizes differed significantly within either type of trial or between the two types of trials, and no evidence of trend according to study size.

Figure 3

Effect of statin therapy on cardiac arrest.

Figure 3

Effect of statin therapy on cardiac arrest.

Sudden cardiac death

Thirty trials reported a total of 2874 sudden cardiac deaths (nine trials had not previously published such information).35,37,38,41,43,47,55,56,58 In the 25 statin vs. control trials for which data were available, statin therapy was associated with a significant 10% proportional reduction in the risk of sudden cardiac death (1131 vs. 1252; OR = 0.90; 95% CI 0.82–0.97, P = 0.01) with no good evidence of heterogeneity between the trials (P = 0.09; Figure 4). Including the additional five trials of intensive vs. standard dose had little effect on the size of the estimated OR (overall OR = 0.89; 95% CI 0.82–0.96; P = 0.002; Figure 4). There was no evidence that the proportional risk reduction differed significantly between the two types of trial. In the trials of statin vs. control, there was some evidence of trend (P = 0.01) towards apparently larger proportional risk reductions among the smaller trials, driven by an apparent lack of benefit in two large trials of patients with heart failure, which had also failed to show any overall effect on cardiovascular outcomes.46,48

Figure 4

Effect of statin therapy on sudden cardiac death.

Figure 4

Effect of statin therapy on sudden cardiac death.

Of the 25 trials of statin vs. control that provided data on sudden cardiac death, 24 also provided data on all cardiac death, and hence, the numbers of patients having other (i.e. non-sudden) cardiac death could be calculated. Compared with the 10% proportional reduction in sudden cardiac death seen in these 24 trials (1115 vs. 1227; OR = 0.90, 99% CI 0.81−1.01, P = 0.02), there was a significant 22% proportional reduction in the risk of other ‘non-sudden’ cardiac death (1235 vs. 1553; OR = 0.78 99% CI 0.71–0.87; P < 0.001; P-value for difference in effect size between the two outcomes = 0.02; Figure 5). Consequently, statin therapy was associated with a significant 17% proportional reduction in the risk of all cardiac death (2350 vs. 2780; OR = 0.83, 95% CI 0.78–0.88; P < 0.001; Figure 5). Inclusion of the additional more vs. less intensive statin therapy trials did not materially affect the size of the estimated ORs for other non-sudden cardiac death (29 trials, 1408 vs. 1754; OR = 0.79; 95% CI 0.74–0.85; P < 0.001).

Figure 5

Effect of statin therapy on sudden cardiac death compared with other (non-sudden) cardiac death.

Figure 5

Effect of statin therapy on sudden cardiac death compared with other (non-sudden) cardiac death.

Adjusting the effect seen in each trial for the LDL-cholesterol difference achieved in each trial60 had no notable impact on any of the findings (results available on request).

Discussion

This study is the most comprehensive meta-analysis of the effect of statin therapy on ventricular arrhythmic events collecting both published and unpublished information from a large set of randomized controlled trials. While we found no evidence that statin therapy significantly reduced the risk of ventricular tachyarrhythmia or of cardiac arrest, the risk of sudden cardiac death was reduced by 10% compared with a reduction in the risk of other (non-sudden) cardiac deaths of about 20%.

Are these findings compatible with a direct anti-arrhythmic effect of statins? Sudden cardiac death is a clinical syndrome that can be caused either primarily by arrhythmia, i.e. a primary electrical event, or by acute coronary events complicated by arrhythmia.3,4 In clinical studies, it is difficult to distinguish between the two causative mechanisms (and some non-cardiac events may in fact have been misclassified as sudden cardiac death). However, autopsy studies suggest that in the general population, at least a third of people diagnosed with sudden cardiac death will have evidence of acute coronary occlusion with a further third showing evidence of plaque erosion.2,61–63 Since statins reduce the risk of acute coronary events, one might expect a reduction in sudden cardiac death due solely to effects on lipid-lowering. It is unclear what magnitude risk reduction this might translate to however and, consequently, we cannot exclude the possibility of some direct anti-arrhythmic effect of statins existing. However, the observation that the reduction in risk of sudden cardiac death was only half of that for other (mostly atherosclerotic) cardiac death, together with the lack of evidence for any effect on ventricular tachyarrhythmia, does not lend much support to any clinically relevant direct ventricular anti-arrhythmic benefit.

Our findings contrast with the previous suggestion that statins reduce the risk of ventricular tachyarrhythmia by about one-third.14–18,45 This could be due to residual confounding and other inherent biases in the previous non-randomized studies14–18 together with large random errors in the one small randomized controlled trial to have directly tested this hypothesis.45 Similarly, in a previous meta-analysis of randomized controlled trials of 10 trials and only 750 events, it was estimated that statins reduce the risk of sudden cardiac death by about one-fifth.64 However, that meta-analysis included only published results and in total included only about one-third as many sudden cardiac deaths as the current study (which also sought to include unpublished data, thereby avoiding the biases that can be introduced by the favourable publication of apparently promising findings).65,66

Study limitations

Most non-fatal arrhythmic events reported in the various included trials were collected from adverse event forms and had not undergone the same rigorous evaluation as in published reports and not based on a unified definition. Although such procedures may have resulted in underestimation of the true number of events and introduced some random errors, they are unlikely to have introduced any bias because underreporting and lack of independent confirmation of the events would be expected to have affected both study groups equally.19,67,68 Nevertheless, the relatively limited number of cardiac arrests and ventricular tachyarrhythmia in the current report, in addition to any random errors resulting from the lack of a unified definition, means that a small benefit (or harm) of statins on these outcomes cannot be ruled out. Further evidence from adequately powered randomized controlled trials would therefore be needed to demonstrate whether any true benefits may exist.

Conclusions

Reducing LDL cholesterol with a statin reduces the risk of sudden cardiac death but the proportional benefit is small compared with that seen for other fatal cardiac events and may be explained by ‘upstream’ anti-atherosclerotic lipid-lowering effects. By contrast, there is no direct evidence that statins significantly reduce the risk of ventricular tachyarrhythmia.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. KR is supported by a senior fellowship from the Oxford Martin School. J.E. acknowledges support from the British Heart Foundation Centre of Research Excellence, Oxford (RE 08/04). K.R. and J.E. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest: none declared.

Acknowledgements

We are grateful to the following people for their support and provision of unpublished data: 4D: Vera Krane, Christoph Wanner; ALERT: Hallvard Holdaas; ALLIANCE: Michael Koren; ASPEN: Robert Knopp; CARDS: Executive committee: Helen Colhoun, D. John Betteridge, Paul Durrington, John H. Fuller, Graham Hitman, Andrew Neil; study statistician: Shona Livingstone; study funders: Pfizer, NHS, and Diabetes UK; CLARIDI: Johan De Sutter; GISSI-P: Roberto Marchioli; Furio Colvicchi; HPS and SEARCH: Rory Collins, Jane Armitage; IDEAL: Terje Pederson; JUPITER: Paul Ridker; LEADe: Howard Feldman; MEGA: Haruo Nakamura, Shinji Hirosaki; METEOR: Michiel L. Bots; NEDIAT: Bernd Stegmayr; PCAB: Haruo Makuuchi; Pfizer: David Demicco, Luz Cubillos, Rana Fayyad; PREVEND-IT: Folkert Asselbergs; PROVE-IT: Chris Cannon, Sabina A. Murphy, Sara Sloan; REVERSAL: Steven E. Nissen; TNT: John LaRosa; and Paul McGale (data extraction).

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Supplementary data

Comments

2 Comments
Statins and Ventricular Arrhythmias: Does it really end here?
26 February 2012
Tahmeed Contractor

Dear Editor,

I read with great interest the recently published meta-analysis by Rahimi et al. In their meta-analysis of randomized controlled trials comparing statins with no statin or intensive versus non-intensive statin therapy, they found no reduction in the risk of ventricular tachycardia and a modest (10%) reduction in sudden cardiac death. The authors conclude that the previously ascribed anti-arrhythmic effect of statins could not be substantiated.

There are several issues with drawing such a conclusion from this meta-analysis. The overall event rate for ventricular arrhythmias is extremely low in the included trials. Most of the reported VT events are from adverse event forms which were not published and hence very unreliable when compared to clinical trials that measure ventricular arrhythmias as a primary or secondary outcome. Also, only a few trials primarily included patients with know risk factors for VT such as low ejection fraction. Hemodynamically stable, brief VT episodes, which portend a poor prognosis, can be accurately recorded only with devices such as implantable cardioverter-defibrillators (ICDs). There was only one small study (n=106) that included subjects with ICDs in the current meta- analysis. The ideal clinical trial, atleast as an initial step, to assess 'anti-arrhythmic' efficacy of statins should include patients at a higher risk for VT (such as cardiomyopathy or prior VT) that have implantable cardioverter-defibrillators and specifically measure ventricular arrhythmia episodes as an outcome. This will ensure an adequate event rate, an excellent means of capturing these events as well as reliability of the outcomes measured. All of these attributes are missing from most trials included in the current meta-analysis. An example of such a trial is CLARIDI (1), that demonstrated a reduction in ICD therapy for ventricular arrhythmias with statin therapy in subjects with CAD. The drastic difference in results of this meta-analysis when compared to previous studies as well as a meta-analysis (2) is likely due to the aforementioned reasons.

References:

1. De Sutter J, De Bacquer D, Jordaens L, De Buyzere M, Matthys K, De Backer G, Tavernier R. Intensive lipid-lowering therapy and ventricular arrhythmias in patients with coronary artery disease and internal cardioverter defibrillator implants: the CLARIDI trial [abstract]. Heart Rhythm 2006;3:1126.

2. Wanahita N, Chen J, Bangalore S, Shah K, Rachko M, Coleman CI, Schweitzer P. The effect of statin therapy on ventricular tachyarrhythmias: a meta-analysis. Am J Ther 2012;19:16-23.

Conflict of Interest:

None declared

Submitted on 26/02/2012 7:00 PM GMT
Collective evidence does not support a substantial direct effect of statins on arrhythmic events: response to readers' comments
26 February 2012
Kazem Rahimi (with Jonathan Emberson)

Dear Editor

Non-randomized comparisons and randomized trials with few events are not well suited to providing reliable estimates of moderate but clinically important effect sizes (e.g. in the range of a 20% proportional risk reduction). The former is prone to significant bias and the latter to large random errors, which, together with the tendency for studies showing apparently large treatment benefits to be more likely to be published, makes any causal inferences of modest effect sizes highly unreliable. In an attempt to overcome such limitations of the existing literature we collected both published and unpublished data from all large-scale randomized trials (1). As acknowledged in the paper, our approach may still have missed a modest effect on ventricular tachyarrhythmia since the total number of events for this outcome remained relatively small (212 [statin] vs 209 [control], OR 1.02 [95% CI 0.84 - 1.25). Nevertheless, this is still the most reliable evidence to date, increasing the evidence from CLARIDI by a factor of ten (11 [statin] vs 20 [control]). While we agree that the use of more sensitive tools such as ICDs may have increased the absolute number of events, this would not be expected to have influenced the estimated proportional effect of treatment. There is also no evidence to suggest that routine reporting of events by investigators as part of adverse reporting in large-scale double-blinded randomised trials renders such events unreliable.(2) If anything, one could argue that such events are more likely to be clinically relevant than an arbitrarily set criteria for classification of largely asymptomatic ICD events.(3) We accept that only a minority of the studies included patients at high risk of ventricular tachyarrhythmia but those that did made the largest contribution to the event rates and there was no suggestion that relative effects were different in higher risk populations (such as GISSI- HF). Our study should not be considered as providing definitive evidence against any direct anti-arrhythmic effect of statins, but the collective evidence from this study and others (4) casts doubt over any substantial effects of statins on arrhythmic events.

REFERENCES

1. Rahimi K, Majoni W, Merhi A, Emberson J. Effect of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evidence from randomized trials. European Heart Journal. 2012 February 3, 2012.

2. Pogue J, Walter SD, Yusuf S. Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs. Clinical Trials. 2009 June 1, 2009;6(3):239-51.

3. Rahimi K, Malhotra A, Banning AP, Jenkinson C. Outcome selection and role of patient reported outcomes in contemporary cardiovascular trials: systematic review. BMJ. 2010;341.

4. Rahimi K, Emberson J, McGale P, Majoni W, Merhi M, Asselbergs FW, et al. Effect of statins on atrial fibrillation: collaborative meta- analysis of published and unpublished evidence from randomised controlled trials. BMJ. 2011;342:d1250.

Conflict of Interest:

None declared

Submitted on 26/02/2012 7:00 PM GMT