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STATINS FOR COPD:

SHOULD WE BE LOOKING AT CRP?

http://ourfightagainstcancer.com/wp-content/uploads/2011/10/lung.jpg

Brady J. Helmink, Pharm.D.

PGY1 Pharmacy Resident

University Medical Center Brackenridge – Seton Healthcare Family

University of Texas at Austin College of Pharmacy

October 11, 2013 Objectives:

1. Describe the mechanisms of statin pleiotropy

2. Explain the potential benefits of statin use in COPD in current literature

3. Define the relationship between CRP, COPD, and cardiovascular disease

4. Recognize future direction of statin use and the role of CRP in COPD

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1. Introduction1-3

a. An estimated 15 million people (6%) in the United States are diagnosed with COPD

b. In 2008, COPD became the third leading cause of death in the United States, claiming the lives

of over 130,000 Americans

c. Hospitalization discharges with a primary diagnosis of COPD occurred in 23.2 per 100,000

patients in 2010

d. Total costs related to COPD in the United States are nearly $50 billion per year, including $25.9

billion in direct healthcare expenditures

2. Definition3

a. COPD is a disease characterized by persistent, progressive airflow limitation associated with an

enhanced chronic inflammatory response of the airways and lungs

b. Chronic inflammation causes narrowing of the small airways and destruction of the lung

parenchyma, causing an inability of the airways to remain open during expiration

c. Characteristic symptoms include chronic cough, progressive dyspnea, sputum production, and

wheezing

d. Exacerbations are events characterized by acute worsening of respiratory symptoms and are

usually more frequent with increased disease severity

e. Patients are diagnosed and classified according to spirometry, symptom scales and

exacerbation risk

Table 1. Classification of COPD3

Patient Group

GOLD Stage* Symptoms Exacerbations

(Per Year) mMRC CAT

A 1 or 2 Less 0 to 1 0 to 1 <10

B 1 or 2 More 0 to 1 ≥2 ≥10

C 3 or 4 Less ≥2 0 to 1 <10

D 3 or 4 More ≥2 ≥2 ≥10 mMRC, Modified British Medical Research Council questionnaire; CAT, COPD Assessment Test

*Based on FEV1/FVC and FEV1 predicted

3. Risk factors3,4

a. Cigarette smoking is the most studied, but there is evidence from epidemiologic studies that

nonsmokers may also develop COPD through exposure to particles including:

i. Organic/inorganic dusts, chemical agents, and fumes

ii. Wood, animal dung, crop residues, and coal burned in open fires

iii. Urban air pollution such as fossil fuel combustion

iv. Passive exposure to cigarette smoke

b. Other risk factors include aging, genetic predisposition, low socioeconomic status, asthma,

chronic bronchitis, and a history of severe respiratory infections

Chronic Obstructive Pulmonary Disease (COPD)

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4. Pathogenesis3

a. Several different mechanisms can amplify the inflammatory response in patients with COPD

i. Oxidative stress results from cigarette smoke and other inhaled particles

ii. Protease-mediated destruction of elastin, a major component in lung parenchyma

important for lung function

iii. Increased numbers of inflammatory cells including CD8+ T lymphocytes, neutrophils,

and macrophages, all of which release inflammatory mediators

iv. Inflammatory mediators including cytokines and growth factors may induce structural

changes and irreversible damage to the airways

5. Pathophysiology3,5

a. The underlying disease process in COPD involves physiologic abnormalities and symptoms

including:

i. Airflow limitation and air trapping correlating with a reduction in forced expiratory

volume in one second/forced vital capacity (FEV1/FVC)

ii. Gas exchange abnormalities resulting in hypoxemia and/or hypercapnia

iii. Mucus hypersecretion resulting in a chronic productive cough

iv. Pulmonary hypertension may occur due to hypoxic vasoconstriction of small

pulmonary arteries

v. Exacerbations of respiratory symptoms are often triggered by bacterial or viral

pathogens and environmental pollutants

6. Therapeutic Options3

a. Smoking cessation has the greatest capacity to influence the natural history of COPD

b. There are currently no existing medications that have been proven to modify long-term

decline in lung function; however, some have shown benefits including reduced exacerbations,

hospitalizations, and symptoms, as well as improvements in FEV1

Table 2. Pharmacologic Treatment Options for COPD3

Patient Group First Line Therapy Alternative Therapy Other Possible Treatments

A SAMA prn or

SABA prn

LAMA or LABA or

SABA and SAMA Theophylline

B LAMA or

LABA LAMA and LABA

SABA and/or SAMA Theophylline

C ICS + LABA or

LAMA

LAMA and LABA or LAMA and PDE4-inh. or

LABA and PDE4-inh.

SABA and/or SAMA Theophylline

D ICS + LABA and/or

LAMA

ICS + LABA and LAMA or ICS + LABA and PDE4-inh. or

LAMA and LABA or LAMA and PDE4-inh.

Carbocysteine SABA and/or SAMA

Theophylline

SAMA, short-acting muscarinic antagonist; SABA, short-acting beta-agonist; LAMA, long-acting muscarinic antagonist; LABA, long-acting

beta-agonist; ICS, inhaled corticosteroid; PDE4-inh., phosphodiesterase-4 inhibitor.

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1. Pleiotropic effects6-10

a. Studies suggest statins have several mechanisms of action independent of their cholesterol-

lowering effects including:

i. Anti-inflammatory actions including reductions in C-Reactive Protein (CRP)

ii. Immunodulatory effects through reduction of inflammatory cytokines

iii. Antioxidant properties by increasing the bioavailability of nitric oxide

iv. Improvement in endothelial dysfunction through inhibition in Rho isoprenylation,

leading to enhanced nitric oxide production

v. Stabilization of atherosclerotic plaques through direction inhibition of MMPs

Figure 1. Proposed Mechanisms of Statin Pleiotropy11

CRP, C-reactive protein; IL-6, interleukin-6; COX-2, cyclooxygenase-2; NO, nitrous oxide; LDL, low-density lipoprotein; ROS, reactive oxygen species;

TNF-α, tumor necrosis factor-alpha; IL-8, interleukin-8; Thc, t-helper cell; MHC-II, major histocompatibility class II; ICAM-1, intracellular adhesion

molecule-1; MMPs, matrix metalloproteinases.

2. Evidence supporting the use of statins in specific disease states7

a. Through the mechanisms listed above, statins have been shown to have potential therapeutic

effects in the following disease states:

a. Alzheimer’s dementia

b. Cancer

c. Stroke

d. Asthma

e. Multiple Sclerosis

f. Heart Failure

g. Sepsis

h. Autoimmune disorders

Pleiotropic Effects of Statins

Statins

Anti-inflammatory Antioxidant

↑ Endothelial

function Immunomodulatory

↓Adhesion

↓CRP, ↓IL-6,

↓COX-2

↑NO,

↓LDL oxidation ↓ROS

↓TNF-α, ↓IL-8,

↓Thc, ↓MHC-II

↓ICAM-1,

↓MMPs

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1. Researchers have investigated the use of statins in COPD while targeting a variety of outcomes

including FEV1 measurements, COPD exacerbations, hospitalizations due to COPD, and mortality

a. Reduction in the decline of FEV112

i. A direct relationship exists between the severity of COPD and the cost of care for

patients with COPD

ii. Due to the role of spirometry in the classification of the disease severity, a decline in

FEV1 is important to monitor and attenuate if possible

Keddissi et al. (2007) The use of statins and lung function in current and former smokers

12

Study objective

Evaluate the effects of statins on the decline in lung function in a population at high risk for inflammatory lung disease

Study design Retrospective cohort study in the United States

Patient population

Current smokers and former smokers seen at VA hospital in 2005

Mean age was 66.8 ± 9.3 years

Patients who had two measured pulmonary function tests (PFTs) ≥ six months apart

Patients classified as having obstructive or restrictive spirometry o Obstructive FEV1/FVC < 70% o Restrictive FEV1/FVC > 80% and FVC < 80%

Allocated into two groups based on statin use for at least three months prior to last PFT vs. no use

Interventions

418 patients underwent two or more PFTs ≥ six months apart and were eligible for analysis o 319 patients (76%) had obstructive spirometry o 99 patients (24%) had restrictive spirometry

215/418 patients (51%) were receiving statins

Statin use in order of frequency o Simvastatin (80.9%), lovastatin (11.6%), atorvastatin (5.6%), and fluvastatin (1.9%)

Outcomes Annual decline in FEV1 and FVC

Results

Overall rate of decline in FEV1 in statin group vs. control (negative values denote an increase) o -5 ± 201 vs. 85 ± 171 mL/year (P < 0.0001)

Overall rate of decline in FVC o -46 ± 446 vs. 135 ± 320 mL/year (P < 0.0001)

Rate of decline in FEV1 in obstructive spirometry group o -5 ± 207 vs. 86 ± 168 mL/year (P < 0.0001)

Rate of decline in FVC in obstructive spirometry group o -33 ± 452 vs. 150 ± 328 mL/year (P< 0.0001)

Authors’ conclusion

Statins may have a protective effect on lung function in current and ex-smokers

Comments

Information on specific dose and duration of statin use not described

Majority of patients were men

Patients receiving statins were more likely to have a history of coronary artery disease, dyslipidemia, diabetes, and hypertension

No difference in FEV1 or FVC decline was seen between the different statins used

Lower FEV1 and FVC decline was apparent in both current and former smokers

The Use of Statins in COPD: Review of the Literature

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b. Reductions in COPD exacerbations13-15

i. COPD exacerbations are associated with significant mortality, especially those

requiring hospitalization

ii. Exacerbations can accelerate the decline of lung function, worsen symptoms, and

negatively affect quality of life for patients with COPD

iii. Three studies describe statin use and COPD exacerbations

Wang et al. (2013) Statin use and risk of COPD exacerbation requiring hospitalization

13

Study objective

Evaluate whether statin use is associated with a reduced risk of COPD exacerbation requiring hospitalization, and to assess whether the effect varied by recent initiation of statin therapy, dose, or duration of statin use

Study design Retrospective, nested case-control study in Taiwan

Patient population

Study cohort comprised of 14,316 patients with COPD

Patients ≥ 45 years of age at second COPD outpatient visit

Diagnosis of COPD was identified based on ICD-9 codes and COPD-related medications

Each case matched with up to four controls randomly selected from patients at risk for COPD exacerbation

Interventions

1,584 cases were defined as patients with a primary diagnosis of COPD or pneumonia concurrently accompanied by secondary diagnosis of COPD, who also received statins

Statin use in order of frequency o Atorvastatin (41.8%), simvastatin (24.4%), lovastatin (12.9%), and fluvastatin (12.3%)

Outcomes

Risk of COPD exacerbation associated with: o Any statin use o Current, recent, or past use of statins o Use of low, medium, and high-dose statins o Duration of statin use

Results

Any use of statins vs. non-use o OR adj. 0.70 (95% CI, 0.56-0.88) P < 0.05

Time frame of statin use vs. no use o Current (0-180 days) = OR adj. 0.60 (95% CI, 0.44-0.81) P < 0.05 o Past (181-365 days) = OR adj. 0.60 (95% CI, 0.33-1.10) P = NS o Remote (>365 days) = OR adj. 0.95 (95% CI, 0.67-1.35) P = NS

Dose of statins vs. no use o High-dose OR adj. 0.33 (95% CI, 0.14-0.73) P < 0.05 o Medium-dose OR adj. 0.60 (95% CI, 0.41-0.89) P < 0.05 o Low-dose OR adj. 0.82 (95% CI, 0.48-1.38) P = NS

Risk of COPD exacerbation based on duration of statin use o ≤30 days = OR adj. 0.53 (95% CI, 0.30-0.95) P < 0.05 o 31-90 days = OR adj. 0.76 (95% CI, 0.47-1.23) P = NS o >90 days = OR adj. 0.53 (95% CI, 0.33-0.85) P < 0.05

Authors’ conclusions

Statin use is associated with a decreased risk of COPD exacerbation requiring hospitalization regardless of treatment duration

The benefit is more profound for current statin use and high-dose statins

Comments The mean follow-up period for cases was 2.3 years

Cases were received more COPD medications at baseline than controls

Current statin users had more comorbidities than non-users

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iv. A prospective cohort study (N=70) reported decreased rates of COPD exacerbations

and greater improvements in health-related quality of life scores in patients receiving

statins. This study described the use of specific statin agents and doses14

v. The use of statins in a retrospective cohort of patients with COPD (N=90) revealed a

decreased number of exacerbations and intubations, as well as increased time to first

exacerbation. All statin users remained free of exacerbations for the first five months

of observation, whereas the majority of patients not receiving statins experienced a

COPD exacerbation within the first three months15

c. Reduction in hospitalizations due to COPD12,16,17

i. An outcome of interest due to the possibility of decreasing the costs associated with

hospitalization and improving quality of life for patients with COPD

ii. Three studies published with endpoints of COPD hospitalization or emergency

department (ED) visit in patients receiving statins

Huang et al. (2011) Statin use and hospitalization in patients with chronic obstructive

pulmonary disease: a nationwide population-based cohort study in Taiwan16

Study objective

Investigate the association of statin use and hospitalizations due to COPD

Study design Population-based cohort study in Taiwan

Patient population

18,721 patients newly diagnosed with COPD by ICD-9 codes

Patients identified from National Health Insurance database

Median age was 64 years

Cases matched to controls without any use of statins by age, sex, and medication for COPD

Interventions

6,252 patients received statins after COPD diagnosis

Statin use in order of frequency o Atorvastatin (31.4%), lovastatin (24.6%), simvastatin (19.2%), fluvastatin (10.8%),

pravastatin (8.7%), and rosuvastatin (5.4%)

Outcomes Hospitalization with a primary diagnosis of COPD during follow-up period

Results

Hospitalization rates during follow-up period o 508 (8.1%) patients with COPD hospitalized using statins o 1324 (10.6%) patients with COPD hospitalized not using statins

Hospitalization among patients with COPD using statins vs. no-use o HR 0.66 (95% CI, 0.60-0.74) P < 0.001

Authors’ conclusion

Statin use in patients with COPD was independently associated with a decreased risk of hospitalization

Comments Average follow-up period was 4.58 years

Information on dose and duration of statin use not described

No information collected on COPD classification

iii. A retrospective cohort of patients (N=215) with abnormal baseline spirometry findings

who received statins showed a lower incidence of respiratory-related ED visits and/or

hospitalizations12

iv. Significant reductions in hospitalizations were observed in both high and low-

cardiovascular risk cohorts in a study of patients with COPD receiving statins19

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d. Mortality reduction in patients with COPD18-25

i. An outcome of interest due to the significantly high rate of mortality due to COPD in

both the United States and around the world

ii. Eight studies have been published investigating mortality as a primary endpoint

Lawes et al. (2012) Statin use in COPD patients is associated with a reduction in mortality: a national cohort study

18

Study objective

Assess whether statin use is associated with reduced mortality in patients with COPD

Study design Population-based retrospective cohort study in New Zealand

Patient population

1,687 patients with a discharge diagnosis of first episode of COPD

Patients between 50 and 80 years of age

Divided into two groups based on statin use prior to admission o Statin users: prescriptions for statins in the six months prior to hospitalization o Statin non-users: no prescriptions for statins in the six months prior to hospitalization

Interventions 596 patients (35%) were statin users

545/596 statin users (91%) were prescribed simvastatin, while the remaining 9% were prescribed atorvastatin

Outcomes All-cause mortality

Results

Risk for all-cause mortality o Crude HR 1.03 (95% CI, 0.88-1.20) o Adjusted for age, sex, ethnicity, history of CVD, diabetes, prescriptions for β-blockers and

furosemide as a proxy for heart failure o Adjusted HR 0.69 (95% CI, 0.58-0.84)

Authors’ conclusion

Statin treatment is associated with a reduction in all-cause mortality for patients with COPD

Comments

Follow-up period of four years after hospital discharge

Information on dose, duration, and adherence to statin therapy not described

No information collected on COPD classification

iii. Two retrospective cohort studies (N=2,286; N=118) found similar results of reductions

in 30-day, 90-day, and two-year mortality19,20

iv. A dose-dependent relationship between statin use and reduction in mortality was

reported in two additional retrospective cohort studies (N=330; N=19,058)21,22

v. A nested case-control study (N=946, high-risk; N=4,907, low-risk) and retrospective

cohort (N=617, primary prevention; N=292, secondary prevention) showed significant

reductions in mortality in patients with COPD and cardiovascular disease at baseline,

but also described a similar mortality benefit in patients with low-cardiovascular

risk16,23

vi. One population-based analysis showed a negative relationship between annual statin

sales and mortality from COPD24

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1. C-Reactive Protein (CRP)5,25-26

a. Synthesized and released by the liver into the circulation in response to inflammation

b. Normal serum CRP level is 1 mg/L

c. Populations known to have elevated CRP levels include those experiencing trauma or infection,

and patients with cardiovascular disease (CVD)

2. CRP and CVD27,28

a. PRIME study investigated the predictability of CRP for risk of coronary heart disease (CHD)

i. Results indicated significant increases in relative risks (RRs) of future myocardial

infarction or coronary death in patients with elevated CRP

b. Framingham CHD Risk Score

i. Prediction tool used to estimate ten-year risk for cardiovascular disease based on

existing risk factors for CHD including age, gender, LDL cholesterol, HDL cholesterol,

total cholesterol, smoking status, blood pressure, and diabetes history

ii. Relationship between CRP and Framingham CHD risk score

1. Results indicated CRP is significantly associated with calculated Framingham

CHD risk scores among middle-aged men and women not taking hormone

replacement therapy (HRT)

Figure 2A-B. Relationship between CRP and ten-year Framingham CHD risk score in (A) men and

(B) women not receiving hormone replacement therapy28

3. CRP and COPD29,30

a. In a study of patients with COPD, the Cardiac Infarction Injury Score (CIIS) was used to estimate

a patient’s risk for developing cardiovascular disease in order to determine the relationship

between CRP levels and risk of cardiac injury

i. Results showed a significant correlation between high CRP levels and cardiac injury in

patients with moderate to severe airflow obstruction

b. Another study described the incidence of hospitalizations and mortality due to COPD

i. Patients with COPD and measured baseline CRP levels were followed over eight years

Relationship Between CRP, COPD and Cardiovascular Disease (CVD)

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ii. Incidence of hospitalizations and mortality was recorded

iii. Results showed CRP levels were significantly elevated in patients who were

hospitalized or had died due to COPD

1. Arnaud et al. demonstrated statins reduce production of CRP in human hepatocytes31

2. Decreasing CRP levels is an outcome of interest due to evidence showing elevated serum CRP levels

are associated with increased hospitalizations and mortality due to COPD

3. Three studies in patients with COPD have targeted either baseline CRP levels or changes in CRP

measurements over various study periods32-34

Melbye et al. (2007) Bronchial airflow limitation, smoking, BMI, and statin use are

strongly associated with the CRP level in the elderly. The Tromsø study32

Study objective

Explore the association of CRP levels and airflow limitation in patients with COPD

Study design Population-based, cross-sectional study in Norway

Patient population

Patients > 60 years of age with COPD

COPD diagnosis based on spirometry

Allocated into five groups on the basis of lung function (FEV1 predicted and FEV1/FVC ratio)

Classified as severe, moderate, and mild airflow limitation, pulmonary restriction or normal airflow

Interventions 3877 patients with spirometry and CRP measurements

535/3877 (14%) patients using statins

Outcomes

CRP measurements in each COPD classification vs. normal airflow group

CRP measurements by self-reported diseases and use of medications

Independent predictors of log-CRP

Results

Measured mean CRP levels in the following groups vs. normal airflow group o Restriction 2.5 vs. 1.64 mg/L (P < 0.001) o Mild 1.74 vs. 1.64 mg/L (P = NS) o Moderate 2.21 vs. 1.64 mg/L (P < 0.001) o Severe 3.15 vs. 1.64 mg/L (P < 0.001)

Measured mean CRP levels with statin use vs. no-use: o 1.59 vs. 1.85 mg/L (P < 0.001)

Measured mean CRP levels in cardiovascular disease vs. no cardiovascular disease: o 1.98 vs. 1.77 mg/L (P < 0.005)

Measured mean CRP levels in any obstructive lung disease vs. no obstructive lung disease o 2.35 vs. 1.74 mg/L (P < 0.001)

Regression analysis showed FEV1 predicted and statin use predictive of decreased log CRP (P < 0.001)

Authors’ conclusions

Impaired lung function is a strong predictor of elevated CRP in the elderly

CRP levels reflect the severity of COPD

CRP measurements may be a useful diagnostic tool for COPD

Comments

Information on dose, duration, and specific statins not described

Measured mean CRP levels = 1.26 mg/L in 646 patients who were never smokers, BMI < 30, no reported chronic respiratory or cardiovascular disease

Study relied on patient-reported data for disease states and medication use

Effect of Statins on CRP in Patients with COPD

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Lee et al. (2008) Usefulness of CRP and IL-6 as predictors of outcomes in patients with COPD receiving pravastatin

33

Study objective

Determine if pravastatin improves exercise capacity and whether baseline and changes in CRP levels predicted clinical outcomes in patients with stable COPD

Study design Randomized controlled trial, double-blind, parallel design in the United States

Patient population

Patients aged 40 to 80 years with stable COPD for ≥ three months

COPD diagnosis defined as FEV1 < 80% predicted and FEV1/FVC ratio < 70%

No patients had prior statin use

50/62 (81%) pravastatin patients and 48/63 (76%) in the placebo group were current smokers

Interventions 125 patients with COPD randomized to receive pravastatin 40mg daily or placebo for six months

(n = 62, pravastatin; n = 63, placebo)

Outcomes Improvement in exercise capacity, measured by exercise time on treadmill

Baseline and changes in CRP and IL-6

Results

CRP level in pravastatin group vs. placebo at follow-up o 2.66 ± 2.49 mg/L vs. 3.85 ± 2.56 mg/L (P < 0.05)

Decrease in CRP from baseline to follow-up in pravastatin group o 3.94 ± 3.54 to 2.66 ± 2.49 mg/L (P < 0.05)

Decrease in IL-6 from baseline o 6.25 ± 1.63 to 3.72 ± 0.95 pg/mL (P < 0.05)

Increase in exercise capacity in pravastatin group vs. placebo o 599 ± 323 to 922 ± 328 seconds (P < 0.0001)

Patients with CRP > 3 mg/L (26/53) experienced a significant decrease in CRP levels vs. those with baseline CRP < 3 mg/L (P < 0.0001)

Regression analysis showed changes in log CRP and baseline log CRP significantly correlated with exercise capacity

o Changes in log CRP (P = 0.049; 95% CI -0.56 to -0.01) o Baseline log CRP (P = 0.008; 95% CI 27.56 to 175.08)

Authors’ conclusions

Pravastatin improves exercise capacity in patients with COPD

Change in CRP levels is predictive of improved exercise tolerance

Results reinforce CRP as a surrogate marker for COPD

Comments Only randomized trial for statin use in COPD

Lahousse et al. (2013) Statins, systemic inflammation and risk of death in COPD: The Rotterdam study

34

Study objective

Discover if statins were associated with reduced mortality in patients with COPD and whether the effects differed according to baseline CRP

Study design Nested case-control within a population-based cohort in the Netherlands

Patient population

Patients ≥ 55 years of age with COPD

COPD diagnosis defined as FEV1/FVC ratio < 70%

Classified as a statin user if received at least one prescription for simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, or rosuvastatin

Each case matched to an average of six controls

85% of both cases and controls were either current or former smokers

Interventions 758 patients with COPD who had measured CRP levels and had received statins

363 patients deceased and were determined as cases

Outcomes

Mortality based on duration of statin therapy

Mortality in patients using statins with baseline CRP > 3 mg/L

Cause-specific mortality

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Results

Risk of mortality in patients with CRP ≤ 3 mg/L with varying duration of statin use vs. no use o 1-30 days = OR adj. 0.77 (95% CI, 0.14-4.09) P = 0.756 o 31 days-2 years = OR adj. 0.60 (95% CI, 0.27-1.34) P = 0.212 o > 2 years = OR adj. 0.79 (95% CI, 0.41-1.55) P = 0.496

Risk of mortality in patients with CRP > 3mg/L with varying duration of statin use vs. no use o 1-30 days = OR crude 1.83 (95% CI, 0.29-11.49) P = 0.520 o 31 days-2 years = OR adj. 0.95 (95% CI, 0.33-2.73) P = 0.917 o > 2 years = OR adj. 0.22 (95% CI 0.06-0.74) P < 0.015

Mortality reduction in smokers with CRP > 3 mg/L and > 2 years of statin use vs. no use o OR 0.15 (95% CI 0.04-0.61)

Decreased mortality in patients with > 2 years of statin use vs. no use o OR 0.61 (95% CI 0.38-0.99) P = 0.045

Trend of decreased pulmonary and cardiovascular mortality in patients with > 30 days of statin use vs. no use

o Pulmonary mortality OR 0.37 (95% CI 0.13-1.08) o Cardiovascular mortality OR 0.58 (95% CI 0.33-1.01)

Authors’ conclusions

Patients with CRP > 3 mg/L experienced a decreased risk of mortality with long-term statin use

Long-term statin use is associated with a decreased risk of all-cause mortality in patients with COPD

Comments

Information on dose, duration, and frequency of use of listed statins not described

Cases were more frequently smokers and had a higher prevalence of cardiovascular disease vs. controls

Mortality risk estimates adjusted for use of cardiovascular drugs, antidiabetics and corticosteroids

1. Currently, there are three clinical trials with either a primary or secondary endpoint of change in CRP

levels from baseline in patients with COPD

Table 3. Clinical Trials Exploring the Effects of Statins on CRP Levels35-37

Study title

The effects of simvastatin in patients with chronic obstructive pulmonary disease

34

The effects of atorvastatin treatment in COPD patients

35

Effect of statin therapy on C-reactive protein levels in patients with COPD

36

Study objective

-Determine the effects of two months of therapy with simvastatin in patients with COPD in the United Kingdom

-Determine whether statins have anti-inflammatory effects on the lungs of patients with COPD in Poland

-Determine whether simvastatin will lower the levels of CRP and ET-1 in patients with COPD in the US

Study design -Phase IV, randomized, double-blind, placebo-controlled

-Phase IV, randomized, single-blind, placebo-controlled

-Phase I, randomized, double-blind, placebo-controlled

Inclusion criteria

-Patients 45 to 85 years of age -Diagnosis of COPD, chronic bronchitis, or emphysema -Smoker or ex-smoker with >20 pack year history -FEV1 30-70% predicted -FEV1/FVC <70% -BMI <25kg/m2

-Patients >40 years of age -Patients with mod-severe stable COPD (Stage II-IV) -Patients with FEV1 <80% predicted and FEV1/FVC <70% at visit one -Current or ex-smokers with ≥ten year smoking history

-Patients 40-79 years of age -Medically optimized patients with COPD with measured CRP levels >3mg/L

Studies in the Pipeline

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Exclusion criteria

-Cardiac or pulmonary disease other than COPD -Respiratory infection -Receiving current PO corticosteroids or leukotriene modifying therapy -Severe or uncontrolled co-morbid disease -History of asthma -Patients receiving a statin prior to entry into study

-Clinically significant abnormality at visit one -History of malignancy -Unable to perform spirometry -COPD exacerbation requiring treatment or hospitalization within six weeks -Respiratory tract infection within four weeks -History of asthma -Concomitant pulmonary disease

-Current smoker -COPD exacerbation within two months -Chronic inflammatory disease -Malignancy -Any acute illness -Leukocytosis (>10,000 WBC) -Thrombocytosis (>450,000 platelets) -Recent history of myocardial infarction or angina within six months

Interventions

-Estimated enrollment: N=20 -Patients randomized to receive simvastatin 40mg daily vs. placebo for 2 months

-Estimated enrollment: N=18 -Patients randomized to receive atorvastatin 40mg daily vs. placebo for 12 weeks

-Estimated enrollment: N=40 -Patients randomized to receive simvastatin 40mg daily vs. placebo for 9 weeks

Outcomes

Primary: -Difference in CRP between simvastatin and placebo at 2, 10, 14, and 22 weeks

Secondary: -Change in CRP levels over 12-week period

Primary: -Serum CRP levels at baseline and 9 weeks

1. There is documented evidence of the beneficial effects of statins in COPD

a. A lower rate of decline in FEV1 and FVC

b. Decreased risk for COPD exacerbations

c. Reduction in hospitalizations due to COPD

d. Decreased all-cause mortality

2. Several questions remain to be addressed

a. What patient population would most benefit from the use of statins?

i. Most studies enrolled patients > 40 years of age

ii. Data lacking in younger patients with COPD

b. Which statin agent(s) should be used?

i. Studies have not indicated which statins, if any in particular, have more benefits in

reduction of CRP, mortality, hospitalizations, exacerbations, or improvements in FEV1

measurements

c. Does the potency of LDL-lowering effects or lipophilicity of individual statins correlate with

potency of pleiotropic effects?

i. To date, a variety of statins have been studied but none have investigated amount of

lung tissue penetration or relative potency of pleiotropic effects

Discussion

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Table 4. Properties of Statins Used in Current COPD Literature38,39

*Prices according to HEB Rx Rewards.

d. What duration of therapy is required to yield beneficial effects?

i. Some studies showed beneficial effects with longer duration of therapy (i.e. > two

years) and others have shown benefits after a follow-up period of ten years

ii. Due to the correlation between COPD and CVD, most patients will benefit from

lifelong statin use

e. Other considerations

i. Cost—most statins have a generic product available and, despite the listed prices, are

relatively inexpensive. Simvastatin, lovastatin and pravastatin may be available on $4

and $10 lists at retail pharmacy locations

ii. Side effect profile—statins are fairly well tolerated drugs, with myalgia being the most

common adverse effect

iii. Drug-drug interactions—must be considered due to metabolism by CYP450 enzymes

3. Results from the literature show an apparent relationship between CRP, COPD, and CVD

a. Elevated CRP levels correlate with increased risk of future CV events

b. Framingham CHD risk score significantly correlates with CRP levels

c. CRP levels are increased in patients with COPD and are related to COPD prognosis

Variable Atorvastatin Simvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin

Dose range (mg)

10 to 80 10 to 40 20 to 80 20 to 80 10 to 40 10 to 40

LDL cholesterol reductions (percent)

38 to 54 28 to 41 17 to 33 29 to 48 19 to 40 52 to 63

Solubility Lipophilic Lipophilic Lipophilic Lipophilic Hydrophilic Hydrophilic

Side effects (incidence

<10% unless otherwise

noted)

Diarrhea (5-14) Arthralgia (4-12)

Nausea Muscle pain

Abdominal pain

Constipation Myalgia

Headache

Headache Dyspepsia Abdominal

pain Myalgia

Increased CPK (11) Flatulence Abdominal

Pain Myalgia

N/V Headache Diarrhea Cough Myalgia

Myalgia (2-13) Arthralgia (4-10)

Headache Dizziness Nausea

Cost (30-day supply)*

$56.97 $15.17 $91.47 $29.97 $5 $194.97

Cytochrome P450

metabolism 3A4 3A4, 3A5 2C9 3A4 - Limited 2C9

Helmink │ 15

4. Clinical trials exploring CRP levels in patients with COPD receiving statins indicates this endpoint may

provide future direction for the use of statins in COPD. Questions that need to be addressed in current

research include:

a. Does each individual statin agent lower CRP levels to a different extent, or is the decrease

considered a class effect?

i. Most studies to date have included all patients on any statin agent, so further research

is needed in this area

b. Is there a specific serum CRP level that corresponds to a need for statin therapy?

i. Current literature supports a CRP value of > 3 mg/L as an indicator of increased risk for

hospitalization and death due to COPD

ii. Further validation of a threshold value is necessary to determine patient risk, thus

offering guidance in the treatment of COPD with a statin through measuring CRP levels

5. Despite the amount of evidence supporting the use of statins in COPD, more information is needed

before a recommendation for routine statin use can be made

6. The patient population that would most benefit from adjunctive statin therapy for COPD includes:

a. GOLD stage 3 or 4 (severe or very severe)

b. Baseline CRP level > 3 mg/L

c. Age > 40 years

d. Higher dose of a statin for an extended duration

Helmink │ 16

Table 5. Overview of Literature Detailing the Use of Statins in COPD

Study Comparison Endpoints Results Conclusions

Bando, et al. (2012)

Use of statins vs. no use Airflow limitation 2/89 patients (2.25%) vs. 64/609 patients (10.51%) P <0.01

The prevalence of airflow limitation in patients using statins was five times lower than patients who did not use statins

Bartziokas, et al. (2011)

Statin use vs. no use Statin use vs. no use Statin use vs. no use Statin use vs. no use Statin use vs. no use

30-day mortality 1-year mortality ECOPD Severe ECOPD HRQoL

HR adj. 0.45 (95% CI, 0.10-2.02) P =0.296 HR adj. 0.85 (95% CI, 0.27-2.69) P =0.768 HR adj. 0.66 (95% CI, 0.45-0.95) P =0.024 HR adj. 0.61 (95% CI, 0.38-0.97) P =0.038 Improvement in all domains (symptoms, activity, impact) and total score P <0.001

Statin use was not related to survival benefit after hospitalization with ECOPD Statin use was associated with a decrease in exacerbations and improvement in HRQoL

Blamoun, et al. (2008)

No statins vs. statin use No statins vs. statin use Statin use vs. non-use Statin use vs. non-use

Exacerbations Intubations Time to exacerbation Time to intubation

OR adj. 2.35 (95% CI, 1.01-5.50) OR adj. 10.36 (95% CI, 2.77-38.76) HR 0.19 (95% CI, 0.06-0.14) HR 0.14 (95% CI, 0.10-0.30)

Statin use was associated with lower incidence of both exacerbations and intubations in patients with COPD

Frost, et al. (2007)

Retrospective cohort Case-control study

Statin <4mg/day vs. no use Statin >4mg/day vs. no use Statin <4mg/day vs. no use Statin >4mg/day vs. no use

COPD hospital mortality

OR adj. 0.58 (95% CI, 0.17-0.92) OR adj. 0.17 (95% CI, 0.07-0.42) OR adj. 0.60 (95% CI, 0.26-1.36) OR adj. 0.19 (95% CI, 0.08-0.47)

Statin use at moderate-high doses was associated with a significant reduction in mortality from COPD

Ishida, et al. (2007)

Across prefecture correlation: statin sales and COPD mortality

COPD mortality Annual statin sales negatively correlated with mortality from COPD (R = 0.574; P<0.001)

Statin use correlated with decreased mortality from COPD

Mancini, et al. (2006)

High-CV risk cohort Low-CV risk cohort

Statin use vs. no use Statin use vs. no use Statin use vs. no use Statin use vs. no use

COPD hospitalization All-cause mortality COPD hospitalization All-cause mortality

RR adj. 0.71 (95% CI, 0.56-0.91) RR adj. 0.53 (95% CI, 0.43-0.65) RR adj. 0.71 (95% CI, 0.64-0.77) RR adj. 0.49 (95% CI, 0.41-0.58)

Statin use is associated with reduced hospitalization and death due to COPD, regardless of CV risk

Appendix

Helmink │ 17

Study Comparison Endpoints Results Conclusions

Sheng, et al. (2012)

Use of statins vs. non-use (primary prevention cohort) Use of statins vs. non-use (secondary prevention cohort)

All-cause mortality

HR adj. 0.61 (95% CI, 0.43-0.85) HR adj. 0.58 (95% CI, 0.35-0.97)

Statin use is associated with improved survival in patients with COPD, regardless of CVD risk

Soyseth, et al. (2007)

Statin use vs. no use All-cause mortality HR adj. 0.57 (95% CI, 0.38-0.87)

Statin use was associated with improved survival after COPD exacerbation

van Gestel, et al. (2008)

Low-dose statin vs. no use Intensified dose statin vs. no use Total Low-dose statin vs. no use Intensified dose statin vs. no use Total

30-day mortality 10-year mortality

OR adj. 0.77 (95% CI, 0.34-1.74) OR adj. 0.08 (95% CI, 0.01-0.64) OR adj. 0.48 (95% CI, 0.23-1.00) HR adj. 0.66 (95% CI, 0.48-0.91) HR adj. 0.58 (95% CI, 0.40-0.83) HR adj. 0.67 (95% CI, 0.52-0.86)

Statin use was associated with improved short- and long-term survival in patients with COPD and PAD

PP, primary prevention; SP, secondary prevention; HR, hazard ratio; ECOPD, exacerbation of COPD; HRQoL, health-related quality of life; OR, odds

ratio; RR, relative risk

Helmink │ 18

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