Statin Therapy HMGCoA Reductase Inhibitors

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The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in ACS and coronary atherosclerosis has illuminated the role of the potential nonlipid effects of these drugs. Statin

Ability to affect platelet-leukocyte interactions Affect degree of circulating markers of inflammation

Î NO synthesis, inhibit isoprenoids, Î Th2>Th1 Regulate inflammatory cyotkine expression,I ICAM expression

Ability to affect platelet-leukocyte interactions Affect degree of circulating markers of inflammation

Î NO synthesis, inhibit isoprenoids, Î Th2>Th1 Regulate inflammatory cyotkine expression,I ICAM expression

Adjuvant therapy: Anti-inflammatory properties

Ability to affect platelet-leukocyte aggregation Reduction of P-selectin expression Inhibition of TRAP stimulation of protease activated receptors

Clopidogrel

Ability to affect platelet-leukocyte aggregation Reduction of P-selectin expression Inhibition of TRAP stimulation of protease activated receptors

Clopidogrel

Adjuvant therapy: Anti-inflammatory properties

Figure 1-9. Anti-inflammatory effects of adjuvant medical therapy in percutaneous coronary interventions. ICAM, intravascular cell adhesion molecule; IL, interleukin; NO, nitric oxide; Th, helper T cells; TNF-a, tumor necrosis factor-a; TRAP, thrombin receptor agonist peptide.

therapy is thought to affect inflammatory processes contributing to atherosclerosis. Specifically, statins produce "pleiotropic" effects by actions on isoprenoids. By inhibiting the production of isoprenoids, statins interfere with G protein-mediated upregula-tion of transcription factors responsible for inflammatory signaling.57

Statins can affect numerous pathways that contribute to inflammation, including adhesion molecules, cytokines, and a variety of inflammatory cell types. A reduction in the levels of ICAM-1/CD54 and CD18/ CD11a by statins has been shown to occur through reduction of messenger RNA (mRNA) transcript.58 Statins have the ability to downregulate leukocyte mRNA for various cytokines such as IL-6, IL-8, and MCP-1. Statins also affect the balance of helper T lymphocytes by favoring a higher proportion TH2 versus TH1 cells.59 By affecting these pathways, statins may hinder progression of atherosclerotic plaque or avert the onset of an ACS.

Clinically, statins such as atorvastatin and simvas-tatin reduce recurrent ischemia after ACS60 and improve mortality in patients with coronary artery disease.61 Benefits attributed to statin use include lipid-independent effects such as reductions in CRP and serum amyloid A (SAA) with intensive statin therapy over a 16-week period.62,63 Although intensive statin therapy has been found to improve clinical outcomes, patients with lower CRP levels as a result of intensive treatment have fewer clinical events, independent of LDL levels, supporting the premise that control of inflammation in ACS leads to a reduction in clinical events.

The Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study randomly assigned 657 patients to receive intensive statin therapy with either atorvastatin 80 mg or pravastatin 40 mg. Intensive therapy with atorvastatin resulted in a greater reduction in CRP and a corresponding reduction in the progression of atherosclerotic disease as assessed by intravascular ultrasound (IVUS).64

In the context of PCI, statin therapy has been proven to reduce periprocedural complications and to improve short- and long-term outcomes (Table 1-3) (Fig. 1-10). Conceptually, the anti-inflammatory properties of statin therapy may reduce the response to injury induced by PCI and periprocedural complications, including microembolization.65 In contrast to most secondary prevention studies, statin use in the context of PCI has demonstrated a mortality benefit (Fig. 1-11).

Multiple studies have also demonstrated a reduction in the periprocedural CK and CK-MB elevations with statin therapy, which have been shown to predict adverse long-term outcomes. A reduction of myonecrosis resulting from pretreatment with statins before PCI may help to explain the reduction in short- and long-term mortality. In the context of PCI, the benefit of statin therapy appears to be distinct from that observed in the secondary prevention trials. The mechanism of statin-induced reduction in myonecrosis may involve a decrease in the postpro-cedural inflammatory response, as supported by the Atorvastatin for Reduction of MYocardial Damage during Angioplasty—Cell Adhesion Molecules (ARMYDA-CAMs) substudy.66

Table 1-3.

Effect of Statin Therapy on

Percutaneous Coronary Intervention

Study

N

Study Design

Population

Outcomes

Results

Comments

Chan et al98

1552

Prospective,

Elective or

MI or death at 1 yr

Pretreatment with

Statins were especially

nonrandomized

urgent PCI

statins was

effective in those with

associated with

hsCRP in highest

reduced mortality

quartile

at 1 yr and less

Chan et al99

periprocedural MI

5052

Prospective,

Excluded MI or

Death at 30 days and

Statin therapy

No significant differences

nonrandomized;

cardiogenic

at 6 mo after PCI

remained

were noted in

propensity

shock

independent

incidence of nonfatal

analysis used

predictor of

MI or rate of repeat

survival at 30 days

revascularization

and 6 mo

Hong

202

Prospective,

Low EF, PCI

Death, AMI, CVA,

Reduction in 1-yr

Simvastatin use was not

et al100

randomized

for AMI

angiographic

mortality and

an independent

restenosis, repeat

restenosis;

predictor of restenosis

PCI/CABG, LV

improvement in

after PCI. Small study

function

LV function

with incomplete

angiographic follow-up

Gaspardone

223

Prospective,

Stable angina,

CRP level at 24 and

Reduction in

No difference between

et al101

observational,

normal LV

48 hr and primary

primary end point

groups with respect to

nonrandomized;

function,

combined end point

with pretreatment

MI or CV death at

three groups

baseline

of death, MI, and

and post-treatment

6 mo. By 48 hr, CRP

(pretreatment,

normal CRP

TVR at 6 mo

groups driven by

levels in pretreatment

post-treatment,

level

TVR

and post-treatment

none)

groups were not

significantly different.

Small study size.

Schomig

4520

Prospective,

Excluded

All-cause mortality

3585 patients were

Nonrandomized,

et al102

observational

patients >80 yr,

at 1 yr

discharged after

observational study

cardiogenic

PCI on statin and

with potential for bias.

shock, in

had 49% adjusted

No difference noted in

hospital

risk reduction of

TVR rate.

mortality, and

primary outcome

life expectancy

<1 yr

Saia et al103

847

Prospective,

First PCI, no

Event-free survival

30% reduction in

Significant reduction in

randomized to

prior PCI or

at 4 yr; LDL, HDL,

risk of adverse

non-target vessel

fluvastatin or

CABG

total cholesterol

cardiac event at

revascularization was

placebo, intention

4 yr after PCI vs.

noted in the statin

to treat

placebo

group

Pasceri

153

Prospective,

Chronic stable

Periprocedural MI

Significant

Authors postulated the

et al104

randomized to

angina without

after elective PCI

reduction in

effect may be anti

statin vs. placebo 7

previous statin

procedural

inflammatory, reduction

days before PCI

therapy

myocardial injury

in microembolization,

with atorvastatin

and platelet adhesion

Chang

119

Prospective,

ACS patients

24-hr CK-MB elevation

Pretreatment

Nonrandomized, small

et al105

nonrandomized,

undergoing

and 6-mo combined

reduced peri-PCI

sample size, only 64%

comparing

PCI

CV event rate

CK-MB rise and

received GP IIb/IIIa

pretreatment vs.

risk of combined

inhibitors

no pretreatment

CV event rate after

adjusting for

baseline

characteristics

Iwakura

293

Prospective,

First STEMI

Intracoronary

33 Patients with

Single-center,

et al65

observational,

myocardial contrast

pretreatment had

observational study

nonrandomized,

echocardiographic

lower incidence of

could introduce bias.

statin pretreatment

evidence of no-

no-reflow

Possible anti-

vs. no pretreatment

reflow after PCI

inflammatory

effects reduce

microembolization

during PCI

Lee et al106

1658

Prospective,

USA, stable

MACE in the first 6 mo

In those with USA

Authors postulated that

randomized, after

angina, or

and secondary

and stable angina,

the effect is

first PCI in those

silent ischemia

end point of MACE

statin use reduced

independent of lipid-

with "average"

without TVR

the risk of MACE

lowering effects

lipid levels

ACS, acute coronary syndrome; AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CK-MB, creatine kinase MB fraction; CV, cardiovascular; CRP, C-reactive protein; CVA, cerebrovascular accident; EF, ejection fraction; GP, glycoprotein; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; LV, left ventricle; MACE, major adverse cardiac event; MI, myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; TVR, target vessel revascularization; USA, unstable angina.

ACS, acute coronary syndrome; AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CK-MB, creatine kinase MB fraction; CV, cardiovascular; CRP, C-reactive protein; CVA, cerebrovascular accident; EF, ejection fraction; GP, glycoprotein; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; LV, left ventricle; MACE, major adverse cardiac event; MI, myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; TVR, target vessel revascularization; USA, unstable angina.

"D

2nd Quartile (0.14-0.41)

3rd Quartile (0.42-1.10)

Preprocedural CRP (mg/dL)

Figure 1-10. Relationship of preprocedural inflammatory state (C-reactive protein [CRP]) and statin use to periprocedural myocardial infarction (MI). (Redrawn from Chan AW, Bhatt DL, Chew DP, et al: Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation 2003;107:1750-1756.)

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