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Evidence of Pre-Procedural Statin Therapy
Journal of the American College of Cardiology © 2010 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 56, No. 14, 2010 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.04.023
QUARTERLY FOCUS ISSUE: PREVENTION/OUTCOMES Cardiac Intervention and Surgery
Evidence of Pre-Procedural Statin Therapy A Meta-Analysis of Randomized Trials David E. Winchester, MD,* Xuerong Wen, MPH,† Lola Xie, BS,‡ Anthony A. Bavry, MD, MPH* Gainesville, Florida Objectives
The purpose of this study was to summarize the evidence of pre-procedural statin therapy to reduce periprocedure cardiovascular events.
Background
Invasive procedures can result in adverse cardiovascular events, such as myocardial infarction (MI) and death. We hypothesized that statins might improve clinical outcomes when used before invasive procedures.
Methods
We searched the MEDLINE, Cochrane, and clinicaltrials.gov databases from inception to February 2010 for randomized, controlled trials that examined statin therapy before invasive procedures. Invasive procedures were defined as percutaneous coronary intervention, coronary artery bypass grafting (CABG), and noncardiac surgery. We required that studies initiated statins before the procedure and reported clinical outcomes. A DerSimonianLaird model was used to construct random-effects summary risk ratios.
Results
Eight percent of the screened trials (21 of 270) met our selection criteria, which included 4,805 patients. The use of pre-procedural statins significantly reduced post-procedural MI (risk ratio [RR]: 0.57, 95% confidence interval [CI]: 0.46 to 0.70, p ⬍ 0.0001). This benefit was seen after both percutaneous coronary intervention (p ⬍ 0.0001) and noncardiac surgical procedures (p ⫽ 0.004), but not CABG (p ⫽ 0.40). All-cause mortality was nonsignificantly reduced by statin therapy (RR: 0.66, 95% CI: 0.37 to 1.17, p ⫽ 0.15). Pre-procedural statins also reduced post-CABG atrial fibrillation (RR: 0.54, 95% CI: 0.43 to 0.68, p ⬍ 0.0001).
Conclusions
Statins administered before invasive procedures significantly reduce the hazard of post-procedural MI. Additionally, statins reduce the risk of atrial fibrillation after CABG. The routine use of statins before invasive procedures should be considered. (J Am Coll Cardiol 2010;56:1099–109) © 2010 by the American College of Cardiology Foundation
Invasive procedures carry an inherent risk of adverse cardiovascular events including myocardial infarction (MI) and death. These events are not uncommon, and when they occur, they are associated with poor clinical outcomes after both percutaneous and surgical procedures (1– 4). To reduce the risk of adverse events associated with invasive procedures, various interventions have been investigated. For example, beta-blockers have been recommended in high-risk patients undergoing noncardiac surgery (5). However, an updated systematic analysis indicates that although this approach may decrease MI, it comes at a cost of increased nonfatal strokes, with no effect on mortality (6). Similarly, pre-operative cardiac stress testing followed by possible coronary revascularization remains conFrom the *Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida; †Department of Epidemiology and Health Policy Research, University of Florida, Gainesville, Florida; and the ‡College of Medicine, University of Florida, Gainesville, Florida. Supported by an unrestricted grant from the Florida Heart Research Institute. All authors have reported that they have no relationships to disclose. Manuscript received February 8, 2010; revised manuscript received March 23, 2010, accepted April 5, 2010.
troversial as this approach has not been shown to decrease the incidence of periprocedural adverse events (7,8). See page 1110
Statins have been demonstrated to be beneficial when started during an acute coronary syndrome (ACS) (9 –11); however, in most of these trials, the statin was started after percutaneous coronary intervention (PCI). Recent publication of randomized trials specifically exploring the role of statin therapy given before invasive procedures, including PCI and surgery, have added to the available evidence of this important clinical question (12,13). Accordingly, we sought to perform a comprehensive meta-analysis to evaluate whether statins administered before invasive procedures might reduce adverse cardiovascular events. Methods Selection criteria. We selected studies of patients undergoing an invasive procedure with randomization to statin
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therapy versus control, in which control could be: 1) placebo; 2) usual care; or 3) lower dose statin ACS ⴝ acute coronary therapy. Invasive procedures were syndrome defined as PCI, coronary artery CABG ⴝ coronary artery bypass grafting (CABG), or nonbypass grafting cardiac surgical procedures includCI ⴝ confidence interval ing vascular surgery. We required CK-MB ⴝ creatine kinasethat study medications were initimyocardial band ated before the procedure and that MI ⴝ myocardial infarction clinical outcome data were reliably PCI ⴝ percutaneous reported. To maximize search sencoronary intervention sitivity, we used the term percutaRR ⴝ risk ratio neous transluminal coronary angioplasty; however, to focus on contemporary practice, we excluded trials that did not routinely use stents. We excluded studies that examined organ transplantation. Select data from previous meta-analyses that included patient level data were used. In studies with more than 2 intervention groups or 2 ⫻ 2 factorial designs, we used the highest dose statin group versus the lowest dose control group or placebo, if available. We excluded trials of multiple interventions in which the statin intervention could not be isolated and compared with a placebo or standard care group. Literature review. A computerized literature search of the MEDLINE database was conducted without language restriction from inception until February 2010 for randomized clinical trials using the search strategy shown in Figure 1. We also searched the Cochrane database and Clinicaltrials. gov using the MeSH terms and keywords listed in Figure 1, Abbreviations and Acronyms
Figure 1
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which did not identify any additional studies beyond MEDLINE. Outcomes and definitions. The primary outcome was post-procedural nonfatal MI. In PCI trials, a postprocedural event was defined as an elevation of the creatine kinase-myocardial band (CK-MB) assay more than 2 to 3 times the upper limit of normal within 12 to 24 h after the procedure. In surgical trials, post-operative MI was defined as a Q-wave MI during hospitalization. Secondary outcomes were all-cause mortality, revascularization, and atrial fibrillation. Revascularization was defined as ischemic symptoms that resulted in a repeat revascularization procedure. New-onset post-operative atrial fibrillation was confirmed by 12-lead electrocardiogram and was persistent for several minutes. When multiple time instances of atrial fibrillation were reported, we preferentially used the earlier outcome. Data extraction. Data were independently extracted by 3 authors (D.E.W., L.X., A.A.B.). Any discrepancies were resolved by consensus of the authors. When necessary for data or article clarification, personal communication was made with select study authors. Baseline patient characteristics were extracted as well as data about each trial’s intervention, previous statin treatment, and duration of follow-up. For all clinical outcomes, we tabulated the number of events that occurred in each arm of each trial. For non-English articles, we used Google Translator (Google, Inc., Mountain View, California) when possible and research associates who are native speakers of foreign languages otherwise.
Study Selection Flow Diagram
Summary of how the systematic search was conducted and eligible studies were identified. CABG ⫽ coronary artery bypass grafting; PCI ⫽ percutaneous coronary intervention; PTCA ⫽ percutaneous transluminal coronary angioplasty.
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Statistical analysis. We analyzed outcomes by the intention-to-treat method. Cholesterol data were analyzed by Student paired t test. A DerSimonian-Laird model was used to construct random-effects summary risk ratios (RRs). We assessed for heterogeneity between studies by calculating a Cochran’s Q statistic and an I2 statistic and for publication bias by Beggs’ and Egger’s methods (14). To explore the effect of pre-selected covariates on the overall treatment effect, we performed a random-effects metaregression analysis (15). The logarithm of relative risk for MI, weighted by the inverse variance of each study, was regressed against type of statin, mean reduction in lowdensity lipoprotein cholesterol in the treatment group, and the number of days before the procedure that statin therapy was initiated. Trial quality was assessed based on the adequate description of treatment allocation, blinded outcome assessment, and description of losses to follow-up (16). We followed the PRISMA statement for conducting a high-quality meta-analysis (17). All p values were 2-tailed, with statistical significance set at 0.05, and confidence intervals (CIs) were calculated at the 95% level. All analyses were performed using STATA software version 11 (STATA Corporation, College Station, Texas).
Results Baseline characteristics. A total of 270 abstracts were selected for further screening. Figure 1 shows our search strategy, which yielded 21 studies with 4,805 patients
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(12,13,18 –36). PCI was usually performed in an elective setting; however, 4 studies included ACS patients (18,21–23) (Table 1). Various statin drugs and doses were used (Table 2). All patients were statin naïve except for 1 study that included patients on long-term statin therapy (22). In the PCI studies, open-label statin was administered after revascularization, whereas in the noncardiac surgical studies, study assignment was maintained to 30 days of follow-up. Measures of study quality are shown in Table 3. Summarized cholesterol data are shown in Table 4. Post-procedural MI. All PCI studies defined MI as 2 to 3 times the upper limit of normal for CK-MB, although 1 study used a definition of CK-MB greater than the upper limit of normal (25). Most surgical studies required new appearance of Q waves; however, 2 studies defined MI as either a Q-wave MI or an elevation in troponin T more than the upper limit of normal (13,35) and 1 study did not define MI (27). Post-procedural MI was reduced by pre-procedural statin therapy compared with control (RR: 0.57, 95% CI: 0.46 to 0.70, p ⬍ 0.0001) (Fig. 2). Cochran’s Q-statistic for heterogeneity was 13.03 (p ⫽ 0.73), with no evidence of publication bias by Egger’s test (p ⫽ 0.14) or Begg’s funnel plot (Fig. 3). In the PCI cohort, the incidence of postprocedural MI was 7.5% with statin therapy versus 13.3% with control (p ⬍ 0.0001). When the PCI analysis was restricted to trials that defined periprocedural MI as a CK-MB ⬎3 times the upper limit of normal (instead of 2 to 3 times), the reduction in MI persisted (RR: 0.67, p ⫽
Baseline and Follow-Up Duration Table 1 Characteristics Baseline Characteristics and Follow-Up Duration First Author/Trial (Ref. #)
Year
Patients, n
Age, yrs
DM, %
Yun et al. (18)
2009
225/220
64/63
33/30
Urgent PCI for ACS
Patient Population
Follow-Up Duration
Veselka et al. (19)
2009
100/100
68/64
26/25
Elective PCI
1 day
NAPLES II (20)
2009
338/330
64/65
39/37
Elective PCI
1 day
Jia et al. (21)
2009
113/115
65/66
19/22
Urgent PCI for ACS*
ARMYDA–RECAPTURE (22)
2009
192/191
66/66
37/35
Elective PCI or urgent PCI for ACS†
30 days
ARMYDA–ACS (23)
2007
86/85
64/67
29/33
Urgent PCI for ACS
30 days
Kinoshita et al. (24)
2007
21/21
66/67
NR‡
Elective PCI
Bozbas et al. (25)
2007
29/34
57/62
17/21
Elective PCI
1 day
ARMYDA (12)
2004
76/77
64/65
27/19
Elective PCI
30 days
Briguori et al. (26)
2004
226/225
63/62
25/19
Elective PCI
Ji et al. (27)
2009
71/69
65/66
38/38
Elective off-pump CABG
13 days
Berkan et al. (28)
2009
23/23
65/68
35/39
Elective CABG
30 days
Mannacio et al. (29)
2008
100/100
61/59
0/0
Elective CABG
23 days
Song et al. (30)
2008
62/62
62/64
47/52
Elective off-pump CABG
30 days
Tamayo et al. (31)
2008
22/22
68/68
27/41
Elective CABG
2.5 days
ARMYDA-3 (32)
2006
101/99
66/67
32/42
Elective CABG
30 days
Chello et al. (33)
2006
20/20
66/64
0/0
Elective CABG
7 days
Christenson et al. (34)
1999
40/37
63/64
23/24
Elective CABG
12 days
DECREASE-III (13)
2009
250/247
66/66
22/17
Elective vascular surgery
30 days
DECREASE-IV (35)
2009
265/268
65/66
12/9
Elective noncardiac surgery
30 days
Durazzo et al. (36)
2004
50/50
66/68
18/16
Elective vascular surgery
30 days
1 day
6 months
1 day
6 months
Data are formatted as statin arm/control arm. *Percentage of patients with DM was not reported; however, mean hemoglobin A1C was 5.7% and 5.4%, respectively. †44% had unstable angina, 26% had non–ST-segment elevation myocardial infarction, and 29% had ST-segment elevation myocardial infarction. ‡53% had stable angina and 47% had non–ST-segment elevation myocardial infarction. ACS ⫽ acute coronary syndrome; CABG ⫽ coronary artery bypass grafting; DM ⫽ diabetes mellitus; NR ⫽ not reported; PCI ⫽ percutaneous coronary intervention.
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Treatment of Statin Therapy Table 2 Strategy Treatment Strategy of Statin Therapy First Author/Trial (Ref. #)
Statin Arm
Control Arm
Post-Procedure Statin‡
Yun et al. (18)
Rosuvastatin 40 mg, mean 16 h before PCI
Usual care
Rosuvastatin 10 mg/day
Veselka et al. (19)
Atorvastatin 80 mg/day, 2 days before PCI
Usual care
Statin therapy daily
NAPLES II (20)
Atorvastatin 80 mg, 1 day before PCI
Usual care
Atorvastatin 20 mg/day
Jia et al. (21)
Simvastatin 80 mg/day, 7 days before PCI
Simvastatin 20 mg/day
Simvastatin 20 mg/day
ARMYDA–RECAPTURE (22)
Atorvastatin 80 mg, 12 h and 40 mg 2 h before PCI
Placebo
Atorvastatin 40 mg/day
ARMYDA–ACS (23)
Atorvastatin 80 mg, 12 h and 40 mg 2 h before PCI
Placebo
Atorvastatin 40 mg/day
Kinoshita et al. (24)
Atorvastatin 5–20 mg/day, ⱖ2 weeks before PCI*
Atorvastatin 5–20 mg/day*
ND
Bozbas et al. (25)
Pravastatin 40 mg/day, 7 days before PCI
Usual care
Pravastatin therapy daily
ARMYDA (12)
Atorvastatin 40 mg/day, 7 days before PCI
Placebo
Atorvastatin 40 mg/day
Briguori et al. (26)
Any statin ⱖ3 days before PCI†
Usual care
Statin therapy daily
Ji et al. (27)
Atorvastatin 20 mg/day, 7 days before CABG
Placebo
ND
Berkan et al. (28)
Fluvastatin 80 mg/day, 3 weeks before CABG
Placebo
ND
Mannacio et al. (29)
Rosuvastatin 20 mg/day, 7 days before CABG
Placebo
Clinically indicated drugs
Song et al. (30)
Atorvastatin 20 mg/day, 3 days before CABG
Usual care
Atorvastatin 20 mg/day
Tamayo et al. (31)
Simvastatin 20 mg/day, 3 weeks before CABG
Usual care
ND
ARMYDA-3 (32)
Atorvastatin 40 mg/day, 7 days before CABG
Placebo
Atorvastatin 40 mg/day
Chello et al. (33)
Atorvastatin 20 mg/day, 3 weeks before CABG
Placebo
ND
Christenson et al. (34)
Simvastatin 20 mg/day, 4 weeks before CABG
Usual care
ND
DECREASE-III (13)
Fluvastatin 80 mg/day, median 37 days before vascular surgery
Placebo
Study drug until 30-day follow-up
DECREASE-IV (35)
Fluvastatin 80 mg/day, median 34 days before noncardiac surgery
Placebo
Study drug until 30-day follow-up
Durazzo et al. (36)
Atorvastatin 20 mg/day, 4 weeks before surgery
Placebo
Study drug until 30-day follow-up
*In the statin arm, the goal was to achieve a low-density lipoprotein ⬍70 mg/dl and in the control arm goal was ⬍100 mg/dl. †Type and dose determined by operator; atorvastatin 29% (mean dose 22 mg/day), pravastatin 29% (mean dose 32 mg/day), simvastatin 39% (mean dose 24 mg/day), and fluvastatin 3% (mean dose 80 mg/day). In 84% of patients, statin was started ⱖ2 weeks before percutaneous coronary intervention. ‡Therapy given to all patients unless otherwise described. ND ⫽ not described; other abbreviations as in Table 1.
0.003). In the CABG cohort, post-operative MI was 1.4% versus 2.9% (p ⫽ 0.40), and in the noncardiac surgery cohort, post-operative MI was 3.5% versus 7.6% (p ⫽
0.004), respectively, for statin therapy versus control. The findings were strengthened when only placebo-controlled trials were examined (Fig. 4). Metaregression confirmed no
Assessment of Study Quality Components Table 3 Assessment of Study Quality Components
First Author/Trial (Ref. #)
Trial Primary Outcome
Generation of Treatment Assignment
Blinded Outcome Assessment
Completeness of Follow-Up (%)
Yun et al. (18)
Post-procedure MI
ND
ND
100/100
Veselka et al. (19)
Post-procedure MI
ND
No
100/100
NAPLES II (20)
Post-procedure MI
Computer-generated
ND
100/100
Jia et al. (21)
Post-procedure MI
ND
ND
100/100
ARMYDA–RECAPTURE (22)
Adverse events
Random number
Double blind*
100/100 100/100
ARMYDA–ACS (23)
Adverse events
Random number
Yes
Kinoshita et al. (24)
Post-procedure MI
ND
ND
95/100
Bozbas et al. (25)
Post-procedure MI
ND
ND
100/100
ARMYDA (12)
Post-procedure MI
ND
Double blind*
100/100
Briguori et al. (26)
Q-wave MI
Computer-generated
No
100/100
Ji et al. (27)
Atrial fibrillation
Computer-generated
Yes
100/100
Berkan et al. (28)
Inflammatory markers
ND
Double blind*
100/100
Mannacio et al. (29)
Post-operative MI
Computer-generated
Double blind*†
100/100
Song et al. (30)
Atrial fibrillation
Randomization table
ND
100/100
Tamayo et al. (31)
Inflammatory markers
ND
ND
100/100
ARMYDA-3 (32)
Atrial fibrillation
Computer generated
Yes
100/100
Chello et al. (33)
Inflammatory markers
ND
Double blind*†
100/100
Christenson et al. (34)
Thrombocytosis
ND
ND
100/100
DECREASE-III (13)
Myocardial ischemia
Computer-generated
ND†
ND
DECREASE-IV (35)
Adverse events
Computer-generated
No
ND
Durazzo et al. (36)
Adverse events
Computer-generated
Yes
100/100
Data are formatted as statin arm/control arm. *Double-blind trial; however, no specific mention of blinded outcome assessment. †Angiograms, electrocardiograms, echocardiograms, and/or laboratory evaluation were interpreted in a blinded fashion; however, no specific mention of clinical outcome assessment. MI ⫽ myocardial infarction; other abbreviation as in Table 2.
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Summary on LipidData Reduction Table 4 Data Summary on Lipid Reduction Treatment
Placebo
Baseline
Follow-Up
p Value*
Baseline
Follow-Up
LDL cholesterol
126 ⫾ 20.6
96 ⫾ 14.6
0.0018
127 ⫾ 19.3
119 ⫾ 11.6
p Value* 0.098
Total cholesterol
215 ⫾ 29.2
171 ⫾ 17.2
0.0025
212 ⫾ 23.1
194 ⫾ 11.6
0.20
Values are mean ⫾ SD. *Paired t test compared between follow-up and baseline for LDL and total cholesterol. LDL ⫽ low-density lipoprotein.
evidence of heterogeneity based on preselected trial characteristics (Table 5, Fig. 5). Additional outcomes. All-cause mortality was nonsignificantly reduced with pre-procedural statin therapy compared with control (RR: 0.66, 95% CI: 0.37 to 1.17, p ⫽ 0.15) (Fig. 6). Among the PCI studies, repeat revascularization was not observed in the statin arm, whereas there were 6 revascularizations in the control arm (RR: 0.26, 95% CI: 0.06 to 1.24, p ⫽ 0.09). Among the CABG studies, post-operative atrial fibrillation was 19% in the statin arm versus 37% in the control arm (RR: 0.54, 95% CI: 0.43 to 0.68, p ⬍ 0.0001) (Fig. 7).
Figure 2
Discussion Our analysis of 21 randomized trials in 4,805 patients shows that pre-procedural statin therapy is beneficial. Statin therapy initiated approximately 1 to 7 days before PCI reduced post-procedural MI, whereas statin therapy initiated approximately 4 weeks before noncardiac surgical procedures reduced post-operative MI. The absolute risk reduction of post-procedural MI was 5.8% after PCI and 4.1% after noncardiac surgical procedures. Considering all the studies, short-term mortality was nonsignificantly reduced. Among the PCI studies, repeat revascularization was nonsignifi-
RRs for Post-Procedural Myocardial Infarction
Trials that did not report myocardial infarction were excluded from this analysis. The relative size of the data markers indicates the weight of the sample size from each study. CI ⫽ confidence interval; RR ⫽ risk ratio; other abbreviations as in Figure 1.
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Figure 3
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Funnel Plot
Funnel plot by Begg’s method to assess for publication bias in post-procedural myocardial infarction (p ⫽ 0.14).
cantly reduced, and among the CABG studies, atrial fibrillation was significantly reduced with pre-procedural statin therapy.
Figure 4
Optimal statin agent and dose. We demonstrated that pre-procedural statin therapy has robust clinical benefit; however, the difficulty in implementing such therapy hinges
RRs for Post-Procedural Myocardial Infarction in Placebo-Controlled Trials
Statistical analysis was repeated using only placebo-controlled trials. Trials that did not report myocardial infarction were excluded from this analysis. The relative size of the data markers indicates the weight of the sample size from each study. Abbreviations as in Figures 1 and 2.
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Univariable Evaluating for Effect Modification of Statin Therapy on Post-Procedure Myocardial Infarction Table 5 Meta-Regression Univariable Meta-Regression Evaluating for Effect Modification of Statin Therapy on Post-Procedure Myocardial Infarction Potential Modifier
Trials, n
Patients, n
Days on statin before procedure
16
4,458
5
Reduction in LDL cholesterol
Relative Risk (95% Confidence Interval)
p Value
0.99 (0.97–1.01) per 1-day increment
0.40
772
0.92 (0.53–1.59) per 10-mg/dl reduction
0.66
Reference
Agent Atorvastatin
—
—
Rosuvastatin
11
2,686
0.93 (0.42–2.05)
0.84
—
Simvastatin
10
2,269
0.37 (0.03–4.69)
0.40
Pravastatin
10
2,104
0.61 (0.10–3.67)
0.55
Fluvastatin
12
3,271
0.89 (0.43–1.84)
0.73
LDL ⫽ low density lipoprotein.
on the type and dose of statin therapy. Both the PCI and surgical studies used a wide variety of drugs and doses; however, in the PCI studies, 56% of the weight of the analysis came from trials of atorvastatin ⱖ40 mg; for CABG studies, 58% of the analysis involved atorvastatin ⱖ20 mg; and for noncardiac surgical trials, 91% of the analysis involved fluvastatin 80 mg. Interestingly, fluvastatin was able to confer benefit despite having the lowest potency. An advantage of fluvastatin is a long-acting formation, which the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) study investigators stated could serves as a “bridge” during the post-operative period when patients were not receiving oral medications. Alternatively, during this period, statin medications could be given by the nasogastric route (35). It stands to reason that higher potency statin therapy would confer more protection around the time of invasive procedures. The PROVE-IT (Prava-
Figure 5
statin or Atorvastatin Evaluation and Infection Therapy) trial supports this concept, although in that study, statin therapy was started after revascularization (37). Only a dedicated trial specifically exploring the relationship of dose and type of statin therapy before invasive procedures can answer this question. For practice to reflect clinical trials, atorvastatin would be selected before PCI and CABG, whereas fluvastatin would be selected before noncardiac surgical procedures. Optimal timing of statin therapy. It is also unknown how long statin therapy should be initiated before invasive procedures to achieve benefit. The ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) trial demonstrated less post-procedural MI with atorvastatin 80 mg/day initiated 1 week before PCI; however, NAPLES (Novel Approaches for Preventing or Limiting Events) II trial also demonstrated benefit of atorvastatin 80 mg initiated just 1 day before PCI. In the PCI trials,
Metaregression Plot
Plot of univariate metaregression examining the effect of duration of statin therapy before the invasive procedure on the relationship of statin therapy and post-procedural myocardial infarction (MI) (p ⫽ 0.40). Abbreviation as in Figure 2.
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Figure 6
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RRs for Short-Term All-Cause Mortality
Trials that did not report mortality were excluded from this analysis. The relative size of the data markers indicate the weight of the sample size from each study. Abbreviations as in Figures 1 and 2.
all patients were given open-label statin after revascularization; suggesting that the reduction in MI is attributable to the pre-procedural use of statins. None of the surgical trials independently demonstrated a significant reduction in MI; however, DECREASE III and IV displayed a trend toward reduced post-operative MI with fluvastatin XL 80 mg initiated 1 month before surgery. In contrast, ARMYDA-3 did not reveal a benefit with atorvastatin 40 mg/day initiated 1 week before PCI, although that study only enrolled 200 patients. In the noncardiac surgical trials, patients were maintained on their treatment assignment until 30-day follow-up. Accordingly, the reduction in MI in this population may be a combined effect of pre- and post-operative use of statins. In sum, these comparisons seem to suggest that earlier initiation of therapy is an important consideration in preventing post-procedural MI after elective procedures. For unstable patients, short-term administration of a high-dose statin may provide clinical benefit without necessitating a delay in performing an indicated invasive procedure. Again, only a dedicated trial can provide insight into how early statins should be started before an invasive procedure to confer optimal benefit. Beneficial effects of statins. Autopsy studies demonstrate the role of plaque rupture and erosion in the pathophysiology of ACS (38). Statins have pleiotropic effects, which
include modification of atherosclerotic plaques (39,40) and improvement of endothelial function (41– 45). Accumulating data are also highlighting the importance of inflammation in the pathogenesis of atherosclerosis and the ability of statins to reduce inflammatory markers and improve cardiovascular events (46 – 48). Statin side effects. The studies included in our analysis did not report data on adverse statin effects, which precluded us from specifically analyzing these outcomes; however, statin safety has been well documented from other studies. Importantly, statins do not appear to increase the risk of events such as rhabdomyolysis or cancer (49,50). Dedicated studies of statins in surgical patients have also confirmed the safety of these drugs post-operatively (51). Because some statins are metabolized through the cytochrome P-450 system, there has been concern that these medications might attenuate the antiplatelet effects of clopidogrel; however, this does not appear to be the case (52). Direct statin effects on coagulation have also been noted (53), but this has not translated into an increased risk of bleeding (54). In our analysis, all-cause mortality was nonsignificantly reduced from pre-procedural statin therapy, which supports the overall safety of these agents during the periprocedure period. Guideline recommendations. Current guidelines for CABG (55), elective PCI (56), and ACS (57) recommend
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Figure 7
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RRs for Atrial Fibrillation
Trials that did not report atrial fibrillation were excluded from this analysis. Atrial fibrillation was only reported in trials of CABG. The relative size of the data markers indicates the weight of the sample size from each study. Abbreviations as in Figures 1 and 2.
statins for secondary prevention of cardiac events through risk-factor modification. Guidelines for perioperative cardiovascular evaluation before noncardiac surgery state that statins can be considered for patients with intermediate risk factors and that it is reasonable to initiate medication before vascular surgery (5). None of these guidelines specifically recommend the use of statins before invasive procedures for the express purpose of preventing periprocedural complications such as MI and atrial fibrillation. Our analysis adds strength to current recommendations and potentially expands the use of these agents before PCI and surgical procedures. Study strengths. A strength of this analysis is the uniform definition of MI and follow-up among the PCI studies. For example, the PCI studies all reported MI within 1 day. Moreover, nonfatal MI was the primary focus of most of the PCI trials and many of the surgical trials. We also carefully evaluated for heterogeneity by the following means: first, our summary estimate is constructed from a random-effects model due to the inherent differences in patient populations and statins. Second, there was no evidence of overall heterogeneity with formal statistical testing. Third, there was no evidence of subtle differences between trials with metaregression. Specifically, statin type, low-density lipoprotein cholesterol reduction from treatment, and the number of days on statin before the procedure did not appear to affect the summary estimate. Study limitations. We expected one limitation to occur as a result of the control groups being a mixture of placebo and usual care, sometimes including statins at doses lower than
in the intervention groups. However, after restricting the analysis to placebo-controlled trials, there was an even stronger reduction in post-procedural MI, among both the PCI and noncardiac surgery trials. Some of the surgical studies explored different primary outcomes, such as inflammatory markers; therefore, adjudication of clinical event data from these studies might be somewhat less reliable. Most of the studies were good quality; however, some studies did not report generation of treatment assignment or whether outcomes were assessed in a blinded fashion. There was no significant reduction in MI after CABG; however, these were small trials that represented only 4% of the weight of the overall analysis. Moreover, the statins in the CABG studies were lower dose. Therefore, the effect of statins in this population remains understudied. Ultimately, an adequately powered study with long-term follow-up will be necessary to demonstrate whether pre-procedural statins not only reduce MI, but safely reduce mortality across a range of invasive procedures.
Conclusions Statin therapy initiated before invasive procedures reduces post-procedural MI, after both PCI and noncardiac surgical procedures. Statin therapy also reduces post-operative atrial fibrillation. Pre-procedural statin therapy should become an increasingly important strategy to improve the safety of invasive procedures.
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Reprint requests and correspondence: Dr. Anthony A. Bavry, Medical Service, Cardiology Section (111-D), North Florida South Georgia Veterans Health System, 1601 SW Archer Road, Gainesville, Florida 32608. E-mail: [email protected].
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20.
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Vol. 56, No. 14, 2010 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2010.04.023
QUARTERLY FOCUS ISSUE: PREVENTION/OUTCOMES Cardiac Intervention and Surgery
Evidence of Pre-Procedural Statin Therapy A Meta-Analysis of Randomized Trials David E. Winchester, MD,* Xuerong Wen, MPH,† Lola Xie, BS,‡ Anthony A. Bavry, MD, MPH* Gainesville, Florida Objectives
The purpose of this study was to summarize the evidence of pre-procedural statin therapy to reduce periprocedure cardiovascular events.
Background
Invasive procedures can result in adverse cardiovascular events, such as myocardial infarction (MI) and death. We hypothesized that statins might improve clinical outcomes when used before invasive procedures.
Methods
We searched the MEDLINE, Cochrane, and clinicaltrials.gov databases from inception to February 2010 for randomized, controlled trials that examined statin therapy before invasive procedures. Invasive procedures were defined as percutaneous coronary intervention, coronary artery bypass grafting (CABG), and noncardiac surgery. We required that studies initiated statins before the procedure and reported clinical outcomes. A DerSimonianLaird model was used to construct random-effects summary risk ratios.
Results
Eight percent of the screened trials (21 of 270) met our selection criteria, which included 4,805 patients. The use of pre-procedural statins significantly reduced post-procedural MI (risk ratio [RR]: 0.57, 95% confidence interval [CI]: 0.46 to 0.70, p ⬍ 0.0001). This benefit was seen after both percutaneous coronary intervention (p ⬍ 0.0001) and noncardiac surgical procedures (p ⫽ 0.004), but not CABG (p ⫽ 0.40). All-cause mortality was nonsignificantly reduced by statin therapy (RR: 0.66, 95% CI: 0.37 to 1.17, p ⫽ 0.15). Pre-procedural statins also reduced post-CABG atrial fibrillation (RR: 0.54, 95% CI: 0.43 to 0.68, p ⬍ 0.0001).
Conclusions
Statins administered before invasive procedures significantly reduce the hazard of post-procedural MI. Additionally, statins reduce the risk of atrial fibrillation after CABG. The routine use of statins before invasive procedures should be considered. (J Am Coll Cardiol 2010;56:1099–109) © 2010 by the American College of Cardiology Foundation
Invasive procedures carry an inherent risk of adverse cardiovascular events including myocardial infarction (MI) and death. These events are not uncommon, and when they occur, they are associated with poor clinical outcomes after both percutaneous and surgical procedures (1– 4). To reduce the risk of adverse events associated with invasive procedures, various interventions have been investigated. For example, beta-blockers have been recommended in high-risk patients undergoing noncardiac surgery (5). However, an updated systematic analysis indicates that although this approach may decrease MI, it comes at a cost of increased nonfatal strokes, with no effect on mortality (6). Similarly, pre-operative cardiac stress testing followed by possible coronary revascularization remains conFrom the *Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida; †Department of Epidemiology and Health Policy Research, University of Florida, Gainesville, Florida; and the ‡College of Medicine, University of Florida, Gainesville, Florida. Supported by an unrestricted grant from the Florida Heart Research Institute. All authors have reported that they have no relationships to disclose. Manuscript received February 8, 2010; revised manuscript received March 23, 2010, accepted April 5, 2010.
troversial as this approach has not been shown to decrease the incidence of periprocedural adverse events (7,8). See page 1110
Statins have been demonstrated to be beneficial when started during an acute coronary syndrome (ACS) (9 –11); however, in most of these trials, the statin was started after percutaneous coronary intervention (PCI). Recent publication of randomized trials specifically exploring the role of statin therapy given before invasive procedures, including PCI and surgery, have added to the available evidence of this important clinical question (12,13). Accordingly, we sought to perform a comprehensive meta-analysis to evaluate whether statins administered before invasive procedures might reduce adverse cardiovascular events. Methods Selection criteria. We selected studies of patients undergoing an invasive procedure with randomization to statin
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therapy versus control, in which control could be: 1) placebo; 2) usual care; or 3) lower dose statin ACS ⴝ acute coronary therapy. Invasive procedures were syndrome defined as PCI, coronary artery CABG ⴝ coronary artery bypass grafting (CABG), or nonbypass grafting cardiac surgical procedures includCI ⴝ confidence interval ing vascular surgery. We required CK-MB ⴝ creatine kinasethat study medications were initimyocardial band ated before the procedure and that MI ⴝ myocardial infarction clinical outcome data were reliably PCI ⴝ percutaneous reported. To maximize search sencoronary intervention sitivity, we used the term percutaRR ⴝ risk ratio neous transluminal coronary angioplasty; however, to focus on contemporary practice, we excluded trials that did not routinely use stents. We excluded studies that examined organ transplantation. Select data from previous meta-analyses that included patient level data were used. In studies with more than 2 intervention groups or 2 ⫻ 2 factorial designs, we used the highest dose statin group versus the lowest dose control group or placebo, if available. We excluded trials of multiple interventions in which the statin intervention could not be isolated and compared with a placebo or standard care group. Literature review. A computerized literature search of the MEDLINE database was conducted without language restriction from inception until February 2010 for randomized clinical trials using the search strategy shown in Figure 1. We also searched the Cochrane database and Clinicaltrials. gov using the MeSH terms and keywords listed in Figure 1, Abbreviations and Acronyms
Figure 1
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which did not identify any additional studies beyond MEDLINE. Outcomes and definitions. The primary outcome was post-procedural nonfatal MI. In PCI trials, a postprocedural event was defined as an elevation of the creatine kinase-myocardial band (CK-MB) assay more than 2 to 3 times the upper limit of normal within 12 to 24 h after the procedure. In surgical trials, post-operative MI was defined as a Q-wave MI during hospitalization. Secondary outcomes were all-cause mortality, revascularization, and atrial fibrillation. Revascularization was defined as ischemic symptoms that resulted in a repeat revascularization procedure. New-onset post-operative atrial fibrillation was confirmed by 12-lead electrocardiogram and was persistent for several minutes. When multiple time instances of atrial fibrillation were reported, we preferentially used the earlier outcome. Data extraction. Data were independently extracted by 3 authors (D.E.W., L.X., A.A.B.). Any discrepancies were resolved by consensus of the authors. When necessary for data or article clarification, personal communication was made with select study authors. Baseline patient characteristics were extracted as well as data about each trial’s intervention, previous statin treatment, and duration of follow-up. For all clinical outcomes, we tabulated the number of events that occurred in each arm of each trial. For non-English articles, we used Google Translator (Google, Inc., Mountain View, California) when possible and research associates who are native speakers of foreign languages otherwise.
Study Selection Flow Diagram
Summary of how the systematic search was conducted and eligible studies were identified. CABG ⫽ coronary artery bypass grafting; PCI ⫽ percutaneous coronary intervention; PTCA ⫽ percutaneous transluminal coronary angioplasty.
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Statistical analysis. We analyzed outcomes by the intention-to-treat method. Cholesterol data were analyzed by Student paired t test. A DerSimonian-Laird model was used to construct random-effects summary risk ratios (RRs). We assessed for heterogeneity between studies by calculating a Cochran’s Q statistic and an I2 statistic and for publication bias by Beggs’ and Egger’s methods (14). To explore the effect of pre-selected covariates on the overall treatment effect, we performed a random-effects metaregression analysis (15). The logarithm of relative risk for MI, weighted by the inverse variance of each study, was regressed against type of statin, mean reduction in lowdensity lipoprotein cholesterol in the treatment group, and the number of days before the procedure that statin therapy was initiated. Trial quality was assessed based on the adequate description of treatment allocation, blinded outcome assessment, and description of losses to follow-up (16). We followed the PRISMA statement for conducting a high-quality meta-analysis (17). All p values were 2-tailed, with statistical significance set at 0.05, and confidence intervals (CIs) were calculated at the 95% level. All analyses were performed using STATA software version 11 (STATA Corporation, College Station, Texas).
Results Baseline characteristics. A total of 270 abstracts were selected for further screening. Figure 1 shows our search strategy, which yielded 21 studies with 4,805 patients
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(12,13,18 –36). PCI was usually performed in an elective setting; however, 4 studies included ACS patients (18,21–23) (Table 1). Various statin drugs and doses were used (Table 2). All patients were statin naïve except for 1 study that included patients on long-term statin therapy (22). In the PCI studies, open-label statin was administered after revascularization, whereas in the noncardiac surgical studies, study assignment was maintained to 30 days of follow-up. Measures of study quality are shown in Table 3. Summarized cholesterol data are shown in Table 4. Post-procedural MI. All PCI studies defined MI as 2 to 3 times the upper limit of normal for CK-MB, although 1 study used a definition of CK-MB greater than the upper limit of normal (25). Most surgical studies required new appearance of Q waves; however, 2 studies defined MI as either a Q-wave MI or an elevation in troponin T more than the upper limit of normal (13,35) and 1 study did not define MI (27). Post-procedural MI was reduced by pre-procedural statin therapy compared with control (RR: 0.57, 95% CI: 0.46 to 0.70, p ⬍ 0.0001) (Fig. 2). Cochran’s Q-statistic for heterogeneity was 13.03 (p ⫽ 0.73), with no evidence of publication bias by Egger’s test (p ⫽ 0.14) or Begg’s funnel plot (Fig. 3). In the PCI cohort, the incidence of postprocedural MI was 7.5% with statin therapy versus 13.3% with control (p ⬍ 0.0001). When the PCI analysis was restricted to trials that defined periprocedural MI as a CK-MB ⬎3 times the upper limit of normal (instead of 2 to 3 times), the reduction in MI persisted (RR: 0.67, p ⫽
Baseline and Follow-Up Duration Table 1 Characteristics Baseline Characteristics and Follow-Up Duration First Author/Trial (Ref. #)
Year
Patients, n
Age, yrs
DM, %
Yun et al. (18)
2009
225/220
64/63
33/30
Urgent PCI for ACS
Patient Population
Follow-Up Duration
Veselka et al. (19)
2009
100/100
68/64
26/25
Elective PCI
1 day
NAPLES II (20)
2009
338/330
64/65
39/37
Elective PCI
1 day
Jia et al. (21)
2009
113/115
65/66
19/22
Urgent PCI for ACS*
ARMYDA–RECAPTURE (22)
2009
192/191
66/66
37/35
Elective PCI or urgent PCI for ACS†
30 days
ARMYDA–ACS (23)
2007
86/85
64/67
29/33
Urgent PCI for ACS
30 days
Kinoshita et al. (24)
2007
21/21
66/67
NR‡
Elective PCI
Bozbas et al. (25)
2007
29/34
57/62
17/21
Elective PCI
1 day
ARMYDA (12)
2004
76/77
64/65
27/19
Elective PCI
30 days
Briguori et al. (26)
2004
226/225
63/62
25/19
Elective PCI
Ji et al. (27)
2009
71/69
65/66
38/38
Elective off-pump CABG
13 days
Berkan et al. (28)
2009
23/23
65/68
35/39
Elective CABG
30 days
Mannacio et al. (29)
2008
100/100
61/59
0/0
Elective CABG
23 days
Song et al. (30)
2008
62/62
62/64
47/52
Elective off-pump CABG
30 days
Tamayo et al. (31)
2008
22/22
68/68
27/41
Elective CABG
2.5 days
ARMYDA-3 (32)
2006
101/99
66/67
32/42
Elective CABG
30 days
Chello et al. (33)
2006
20/20
66/64
0/0
Elective CABG
7 days
Christenson et al. (34)
1999
40/37
63/64
23/24
Elective CABG
12 days
DECREASE-III (13)
2009
250/247
66/66
22/17
Elective vascular surgery
30 days
DECREASE-IV (35)
2009
265/268
65/66
12/9
Elective noncardiac surgery
30 days
Durazzo et al. (36)
2004
50/50
66/68
18/16
Elective vascular surgery
30 days
1 day
6 months
1 day
6 months
Data are formatted as statin arm/control arm. *Percentage of patients with DM was not reported; however, mean hemoglobin A1C was 5.7% and 5.4%, respectively. †44% had unstable angina, 26% had non–ST-segment elevation myocardial infarction, and 29% had ST-segment elevation myocardial infarction. ‡53% had stable angina and 47% had non–ST-segment elevation myocardial infarction. ACS ⫽ acute coronary syndrome; CABG ⫽ coronary artery bypass grafting; DM ⫽ diabetes mellitus; NR ⫽ not reported; PCI ⫽ percutaneous coronary intervention.
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Treatment of Statin Therapy Table 2 Strategy Treatment Strategy of Statin Therapy First Author/Trial (Ref. #)
Statin Arm
Control Arm
Post-Procedure Statin‡
Yun et al. (18)
Rosuvastatin 40 mg, mean 16 h before PCI
Usual care
Rosuvastatin 10 mg/day
Veselka et al. (19)
Atorvastatin 80 mg/day, 2 days before PCI
Usual care
Statin therapy daily
NAPLES II (20)
Atorvastatin 80 mg, 1 day before PCI
Usual care
Atorvastatin 20 mg/day
Jia et al. (21)
Simvastatin 80 mg/day, 7 days before PCI
Simvastatin 20 mg/day
Simvastatin 20 mg/day
ARMYDA–RECAPTURE (22)
Atorvastatin 80 mg, 12 h and 40 mg 2 h before PCI
Placebo
Atorvastatin 40 mg/day
ARMYDA–ACS (23)
Atorvastatin 80 mg, 12 h and 40 mg 2 h before PCI
Placebo
Atorvastatin 40 mg/day
Kinoshita et al. (24)
Atorvastatin 5–20 mg/day, ⱖ2 weeks before PCI*
Atorvastatin 5–20 mg/day*
ND
Bozbas et al. (25)
Pravastatin 40 mg/day, 7 days before PCI
Usual care
Pravastatin therapy daily
ARMYDA (12)
Atorvastatin 40 mg/day, 7 days before PCI
Placebo
Atorvastatin 40 mg/day
Briguori et al. (26)
Any statin ⱖ3 days before PCI†
Usual care
Statin therapy daily
Ji et al. (27)
Atorvastatin 20 mg/day, 7 days before CABG
Placebo
ND
Berkan et al. (28)
Fluvastatin 80 mg/day, 3 weeks before CABG
Placebo
ND
Mannacio et al. (29)
Rosuvastatin 20 mg/day, 7 days before CABG
Placebo
Clinically indicated drugs
Song et al. (30)
Atorvastatin 20 mg/day, 3 days before CABG
Usual care
Atorvastatin 20 mg/day
Tamayo et al. (31)
Simvastatin 20 mg/day, 3 weeks before CABG
Usual care
ND
ARMYDA-3 (32)
Atorvastatin 40 mg/day, 7 days before CABG
Placebo
Atorvastatin 40 mg/day
Chello et al. (33)
Atorvastatin 20 mg/day, 3 weeks before CABG
Placebo
ND
Christenson et al. (34)
Simvastatin 20 mg/day, 4 weeks before CABG
Usual care
ND
DECREASE-III (13)
Fluvastatin 80 mg/day, median 37 days before vascular surgery
Placebo
Study drug until 30-day follow-up
DECREASE-IV (35)
Fluvastatin 80 mg/day, median 34 days before noncardiac surgery
Placebo
Study drug until 30-day follow-up
Durazzo et al. (36)
Atorvastatin 20 mg/day, 4 weeks before surgery
Placebo
Study drug until 30-day follow-up
*In the statin arm, the goal was to achieve a low-density lipoprotein ⬍70 mg/dl and in the control arm goal was ⬍100 mg/dl. †Type and dose determined by operator; atorvastatin 29% (mean dose 22 mg/day), pravastatin 29% (mean dose 32 mg/day), simvastatin 39% (mean dose 24 mg/day), and fluvastatin 3% (mean dose 80 mg/day). In 84% of patients, statin was started ⱖ2 weeks before percutaneous coronary intervention. ‡Therapy given to all patients unless otherwise described. ND ⫽ not described; other abbreviations as in Table 1.
0.003). In the CABG cohort, post-operative MI was 1.4% versus 2.9% (p ⫽ 0.40), and in the noncardiac surgery cohort, post-operative MI was 3.5% versus 7.6% (p ⫽
0.004), respectively, for statin therapy versus control. The findings were strengthened when only placebo-controlled trials were examined (Fig. 4). Metaregression confirmed no
Assessment of Study Quality Components Table 3 Assessment of Study Quality Components
First Author/Trial (Ref. #)
Trial Primary Outcome
Generation of Treatment Assignment
Blinded Outcome Assessment
Completeness of Follow-Up (%)
Yun et al. (18)
Post-procedure MI
ND
ND
100/100
Veselka et al. (19)
Post-procedure MI
ND
No
100/100
NAPLES II (20)
Post-procedure MI
Computer-generated
ND
100/100
Jia et al. (21)
Post-procedure MI
ND
ND
100/100
ARMYDA–RECAPTURE (22)
Adverse events
Random number
Double blind*
100/100 100/100
ARMYDA–ACS (23)
Adverse events
Random number
Yes
Kinoshita et al. (24)
Post-procedure MI
ND
ND
95/100
Bozbas et al. (25)
Post-procedure MI
ND
ND
100/100
ARMYDA (12)
Post-procedure MI
ND
Double blind*
100/100
Briguori et al. (26)
Q-wave MI
Computer-generated
No
100/100
Ji et al. (27)
Atrial fibrillation
Computer-generated
Yes
100/100
Berkan et al. (28)
Inflammatory markers
ND
Double blind*
100/100
Mannacio et al. (29)
Post-operative MI
Computer-generated
Double blind*†
100/100
Song et al. (30)
Atrial fibrillation
Randomization table
ND
100/100
Tamayo et al. (31)
Inflammatory markers
ND
ND
100/100
ARMYDA-3 (32)
Atrial fibrillation
Computer generated
Yes
100/100
Chello et al. (33)
Inflammatory markers
ND
Double blind*†
100/100
Christenson et al. (34)
Thrombocytosis
ND
ND
100/100
DECREASE-III (13)
Myocardial ischemia
Computer-generated
ND†
ND
DECREASE-IV (35)
Adverse events
Computer-generated
No
ND
Durazzo et al. (36)
Adverse events
Computer-generated
Yes
100/100
Data are formatted as statin arm/control arm. *Double-blind trial; however, no specific mention of blinded outcome assessment. †Angiograms, electrocardiograms, echocardiograms, and/or laboratory evaluation were interpreted in a blinded fashion; however, no specific mention of clinical outcome assessment. MI ⫽ myocardial infarction; other abbreviation as in Table 2.
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Summary on LipidData Reduction Table 4 Data Summary on Lipid Reduction Treatment
Placebo
Baseline
Follow-Up
p Value*
Baseline
Follow-Up
LDL cholesterol
126 ⫾ 20.6
96 ⫾ 14.6
0.0018
127 ⫾ 19.3
119 ⫾ 11.6
p Value* 0.098
Total cholesterol
215 ⫾ 29.2
171 ⫾ 17.2
0.0025
212 ⫾ 23.1
194 ⫾ 11.6
0.20
Values are mean ⫾ SD. *Paired t test compared between follow-up and baseline for LDL and total cholesterol. LDL ⫽ low-density lipoprotein.
evidence of heterogeneity based on preselected trial characteristics (Table 5, Fig. 5). Additional outcomes. All-cause mortality was nonsignificantly reduced with pre-procedural statin therapy compared with control (RR: 0.66, 95% CI: 0.37 to 1.17, p ⫽ 0.15) (Fig. 6). Among the PCI studies, repeat revascularization was not observed in the statin arm, whereas there were 6 revascularizations in the control arm (RR: 0.26, 95% CI: 0.06 to 1.24, p ⫽ 0.09). Among the CABG studies, post-operative atrial fibrillation was 19% in the statin arm versus 37% in the control arm (RR: 0.54, 95% CI: 0.43 to 0.68, p ⬍ 0.0001) (Fig. 7).
Figure 2
Discussion Our analysis of 21 randomized trials in 4,805 patients shows that pre-procedural statin therapy is beneficial. Statin therapy initiated approximately 1 to 7 days before PCI reduced post-procedural MI, whereas statin therapy initiated approximately 4 weeks before noncardiac surgical procedures reduced post-operative MI. The absolute risk reduction of post-procedural MI was 5.8% after PCI and 4.1% after noncardiac surgical procedures. Considering all the studies, short-term mortality was nonsignificantly reduced. Among the PCI studies, repeat revascularization was nonsignifi-
RRs for Post-Procedural Myocardial Infarction
Trials that did not report myocardial infarction were excluded from this analysis. The relative size of the data markers indicates the weight of the sample size from each study. CI ⫽ confidence interval; RR ⫽ risk ratio; other abbreviations as in Figure 1.
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Figure 3
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Funnel Plot
Funnel plot by Begg’s method to assess for publication bias in post-procedural myocardial infarction (p ⫽ 0.14).
cantly reduced, and among the CABG studies, atrial fibrillation was significantly reduced with pre-procedural statin therapy.
Figure 4
Optimal statin agent and dose. We demonstrated that pre-procedural statin therapy has robust clinical benefit; however, the difficulty in implementing such therapy hinges
RRs for Post-Procedural Myocardial Infarction in Placebo-Controlled Trials
Statistical analysis was repeated using only placebo-controlled trials. Trials that did not report myocardial infarction were excluded from this analysis. The relative size of the data markers indicates the weight of the sample size from each study. Abbreviations as in Figures 1 and 2.
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Univariable Evaluating for Effect Modification of Statin Therapy on Post-Procedure Myocardial Infarction Table 5 Meta-Regression Univariable Meta-Regression Evaluating for Effect Modification of Statin Therapy on Post-Procedure Myocardial Infarction Potential Modifier
Trials, n
Patients, n
Days on statin before procedure
16
4,458
5
Reduction in LDL cholesterol
Relative Risk (95% Confidence Interval)
p Value
0.99 (0.97–1.01) per 1-day increment
0.40
772
0.92 (0.53–1.59) per 10-mg/dl reduction
0.66
Reference
Agent Atorvastatin
—
—
Rosuvastatin
11
2,686
0.93 (0.42–2.05)
0.84
—
Simvastatin
10
2,269
0.37 (0.03–4.69)
0.40
Pravastatin
10
2,104
0.61 (0.10–3.67)
0.55
Fluvastatin
12
3,271
0.89 (0.43–1.84)
0.73
LDL ⫽ low density lipoprotein.
on the type and dose of statin therapy. Both the PCI and surgical studies used a wide variety of drugs and doses; however, in the PCI studies, 56% of the weight of the analysis came from trials of atorvastatin ⱖ40 mg; for CABG studies, 58% of the analysis involved atorvastatin ⱖ20 mg; and for noncardiac surgical trials, 91% of the analysis involved fluvastatin 80 mg. Interestingly, fluvastatin was able to confer benefit despite having the lowest potency. An advantage of fluvastatin is a long-acting formation, which the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) study investigators stated could serves as a “bridge” during the post-operative period when patients were not receiving oral medications. Alternatively, during this period, statin medications could be given by the nasogastric route (35). It stands to reason that higher potency statin therapy would confer more protection around the time of invasive procedures. The PROVE-IT (Prava-
Figure 5
statin or Atorvastatin Evaluation and Infection Therapy) trial supports this concept, although in that study, statin therapy was started after revascularization (37). Only a dedicated trial specifically exploring the relationship of dose and type of statin therapy before invasive procedures can answer this question. For practice to reflect clinical trials, atorvastatin would be selected before PCI and CABG, whereas fluvastatin would be selected before noncardiac surgical procedures. Optimal timing of statin therapy. It is also unknown how long statin therapy should be initiated before invasive procedures to achieve benefit. The ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) trial demonstrated less post-procedural MI with atorvastatin 80 mg/day initiated 1 week before PCI; however, NAPLES (Novel Approaches for Preventing or Limiting Events) II trial also demonstrated benefit of atorvastatin 80 mg initiated just 1 day before PCI. In the PCI trials,
Metaregression Plot
Plot of univariate metaregression examining the effect of duration of statin therapy before the invasive procedure on the relationship of statin therapy and post-procedural myocardial infarction (MI) (p ⫽ 0.40). Abbreviation as in Figure 2.
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Figure 6
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RRs for Short-Term All-Cause Mortality
Trials that did not report mortality were excluded from this analysis. The relative size of the data markers indicate the weight of the sample size from each study. Abbreviations as in Figures 1 and 2.
all patients were given open-label statin after revascularization; suggesting that the reduction in MI is attributable to the pre-procedural use of statins. None of the surgical trials independently demonstrated a significant reduction in MI; however, DECREASE III and IV displayed a trend toward reduced post-operative MI with fluvastatin XL 80 mg initiated 1 month before surgery. In contrast, ARMYDA-3 did not reveal a benefit with atorvastatin 40 mg/day initiated 1 week before PCI, although that study only enrolled 200 patients. In the noncardiac surgical trials, patients were maintained on their treatment assignment until 30-day follow-up. Accordingly, the reduction in MI in this population may be a combined effect of pre- and post-operative use of statins. In sum, these comparisons seem to suggest that earlier initiation of therapy is an important consideration in preventing post-procedural MI after elective procedures. For unstable patients, short-term administration of a high-dose statin may provide clinical benefit without necessitating a delay in performing an indicated invasive procedure. Again, only a dedicated trial can provide insight into how early statins should be started before an invasive procedure to confer optimal benefit. Beneficial effects of statins. Autopsy studies demonstrate the role of plaque rupture and erosion in the pathophysiology of ACS (38). Statins have pleiotropic effects, which
include modification of atherosclerotic plaques (39,40) and improvement of endothelial function (41– 45). Accumulating data are also highlighting the importance of inflammation in the pathogenesis of atherosclerosis and the ability of statins to reduce inflammatory markers and improve cardiovascular events (46 – 48). Statin side effects. The studies included in our analysis did not report data on adverse statin effects, which precluded us from specifically analyzing these outcomes; however, statin safety has been well documented from other studies. Importantly, statins do not appear to increase the risk of events such as rhabdomyolysis or cancer (49,50). Dedicated studies of statins in surgical patients have also confirmed the safety of these drugs post-operatively (51). Because some statins are metabolized through the cytochrome P-450 system, there has been concern that these medications might attenuate the antiplatelet effects of clopidogrel; however, this does not appear to be the case (52). Direct statin effects on coagulation have also been noted (53), but this has not translated into an increased risk of bleeding (54). In our analysis, all-cause mortality was nonsignificantly reduced from pre-procedural statin therapy, which supports the overall safety of these agents during the periprocedure period. Guideline recommendations. Current guidelines for CABG (55), elective PCI (56), and ACS (57) recommend
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Figure 7
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RRs for Atrial Fibrillation
Trials that did not report atrial fibrillation were excluded from this analysis. Atrial fibrillation was only reported in trials of CABG. The relative size of the data markers indicates the weight of the sample size from each study. Abbreviations as in Figures 1 and 2.
statins for secondary prevention of cardiac events through risk-factor modification. Guidelines for perioperative cardiovascular evaluation before noncardiac surgery state that statins can be considered for patients with intermediate risk factors and that it is reasonable to initiate medication before vascular surgery (5). None of these guidelines specifically recommend the use of statins before invasive procedures for the express purpose of preventing periprocedural complications such as MI and atrial fibrillation. Our analysis adds strength to current recommendations and potentially expands the use of these agents before PCI and surgical procedures. Study strengths. A strength of this analysis is the uniform definition of MI and follow-up among the PCI studies. For example, the PCI studies all reported MI within 1 day. Moreover, nonfatal MI was the primary focus of most of the PCI trials and many of the surgical trials. We also carefully evaluated for heterogeneity by the following means: first, our summary estimate is constructed from a random-effects model due to the inherent differences in patient populations and statins. Second, there was no evidence of overall heterogeneity with formal statistical testing. Third, there was no evidence of subtle differences between trials with metaregression. Specifically, statin type, low-density lipoprotein cholesterol reduction from treatment, and the number of days on statin before the procedure did not appear to affect the summary estimate. Study limitations. We expected one limitation to occur as a result of the control groups being a mixture of placebo and usual care, sometimes including statins at doses lower than
in the intervention groups. However, after restricting the analysis to placebo-controlled trials, there was an even stronger reduction in post-procedural MI, among both the PCI and noncardiac surgery trials. Some of the surgical studies explored different primary outcomes, such as inflammatory markers; therefore, adjudication of clinical event data from these studies might be somewhat less reliable. Most of the studies were good quality; however, some studies did not report generation of treatment assignment or whether outcomes were assessed in a blinded fashion. There was no significant reduction in MI after CABG; however, these were small trials that represented only 4% of the weight of the overall analysis. Moreover, the statins in the CABG studies were lower dose. Therefore, the effect of statins in this population remains understudied. Ultimately, an adequately powered study with long-term follow-up will be necessary to demonstrate whether pre-procedural statins not only reduce MI, but safely reduce mortality across a range of invasive procedures.
Conclusions Statin therapy initiated before invasive procedures reduces post-procedural MI, after both PCI and noncardiac surgical procedures. Statin therapy also reduces post-operative atrial fibrillation. Pre-procedural statin therapy should become an increasingly important strategy to improve the safety of invasive procedures.
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Reprint requests and correspondence: Dr. Anthony A. Bavry, Medical Service, Cardiology Section (111-D), North Florida South Georgia Veterans Health System, 1601 SW Archer Road, Gainesville, Florida 32608. E-mail: [email protected].
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