TY - JOUR
AU - Sanders, Rhonda, Martin
AB - Abstract Purpose. The impact of C-reactive protein (CRP) on the treatment of patients with cardiovascular disease is described. Summary. CRP is a marker of coronary heart disease and other disease states. Its release from the liver activates endothelial dysfunction and contributes to atherothrombosis. In healthy persons, CRP was found to be an independent risk marker for cardiovascular disease when compared with low-density-lipoprotein (LDL) cholesterol. In 2003, the Centers for Disease Control and Prevention and the American Heart Association published a statement regarding CRP’s use in clinical practice and public health. In a primary prevention study, statins were shown to reduce CRP, and patients with a low concentration of LDL cholesterol and high CRP may benefit from statin therapy. The results of a secondary prevention study confirmed that CRP reduction was not related to the lipid-lowering effects of the statins and that pravastatin reduced coronary events regardless of inflammation status designated by the CRP value. Another study demonstrated that intensive pharmacotherapy was more effective than moderate therapy in reducing CRP, but it found no difference in clinical outcomes among statin regimens once the goal CRP value was attained. In atheroma ultrasound studies, a reduced CRP level was related to reductions in atheroma volume regardless of the statin regimen used. Conclusion. The correct use of CRP in pharmacotherapeutic monitoring of statins has not been fully elucidated. Until more data regarding CRP and statin use are available, pharmacists must continue to focus on risk factors other than CRP, such as cholesterol levels, medical history, social history, and lifestyle characteristics, when making clinical decisions regarding statin therapy. Antilipemic agents, Cardiovascular diseases, C-Reactive Protein, Drugs, Pravastatin C-reactive protein (CRP) and other inflammatory markers were originally studied because half of all patients with myocardial infarction (MI) were found to have normal plasma lipid levels.1 Until the late 1990s, cholesterol was believed to be the best laboratory predictor of cardiovascular events and modifiable risk factor in coronary artery disease.2 Recent data have shown that high-sensitivity CRP (hs-CRP) may be a stronger predictor of MI and ischemic stroke than is low-density-lipoprotein (LDL) cholesterol.3 Some studies have shown that serum CRP measurements are predictive of cardiovascular ischemia and death in patient populations with angina or acute coronary syndrome (ACS).4 In some institutions, CRP levels are monitored in hospitalized patients with angina symptoms. Elevated levels of CRP in healthy patients have been found to be predictive of a first cardiac event and are useful in identifying patients at increased risk for a cardiac event.5,6 Several recently published studies have described the utility of CRP evaluation in the secondary prevention of cardiovascular events.7,–10 To date, little attention has been given to the effect of pharmacotherapy on CRP levels in patients with cardiovascular disease. National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines indicate that inflammatory markers such as CRP are “emerging risk factors” and should be considered in combination with standard risk factors when treating patients.11 The American Heart Association (AHA) provided further direction in a scientific statement, but no specific recommendations were given regarding common pharmacotherapies (e.g., statins) and the evaluation of CRP levels for cardiovascular risk reduction.12 This article reviews the use of CRP for cardiovascular-risk assessment, summarizes findings from major studies of CRP evaluation in the primary and secondary prevention of vascular events, and discusses the limited use that CRP may have in monitoring a patient’s statin therapy. Role of CRP in the inflammatory process CRP, an immune recognition protein primarily formed in the liver, is an acute marker of inflammation in cardiovascular disease.13 The concentration of CRP, a nonspecific acute-phase reactant, becomes elevated in the presence of other acute inflammatory processes, such as infection, inflammatory bowel disease, and immunologic diseases. CRP is also released directly from atherosclerotic plaques. During vascular damage and activation of the immune cells in the atherosclerotic plaques, cytokines, such as tumor necrosis factor and interleukin-6 (IL-6), are released.14 Interleukin-6 stimulates the production of acute-phase reactants, including CRP, from the liver and is also released from adipose tissue in response to infection or metabolic syndrome. As CRP has a short half-life (t½) of five to seven hours, its level will rise rapidly secondary to tissue injury or infection.15 In atherosclerotic disease, the release of CRP contributes to several mechanisms that lead to endothelial dysfunction. CRP can recruit circulating white blood cells, increase LDL cholesterol uptake by macrophages, promote oxidation of circulating LDL cholesterol, and inhibit enzymes that induce natural vasodilation, such as endothelial nitric oxide synthase.13 CRP can also induce the expression of adhesion molecules on endothelial cells, thereby propagating antigens and stimulating monocyte recruitment.16 In addition, CRP can alter the body’s fibrinolytic mechanisms, such as inducing plasminogen activator inhibitor 1, preventing clot dissolution and further contributing to atherothrombosis. Diseases, lifestyle choices, and certain medications can increase CRP levels.12 Inflammation and chronic infection can cause an abrupt increase in CRP concentrations, often to >10 mg/L. Chronic diseases (e.g., hypertension, obesity, diabetes, metabolic syndrome) may also be associated with increased CRP levels. For example, prehypertensive or hypertensive patients who had a CRP concentration of >3 mg/L had a significantly greater risk of having a first cardiovascular event than did control patients.17 Increased CRP levels in obese patients can be related to adipocyte secretion of IL-6.18 Patients with diabetes or metabolic syndrome appear to have higher baseline CRP levels than healthy persons and have at least twice the risk of developing coronary heart disease (CHD).19 Oral hormone replacement therapy (HRT) has been shown to increase CRP levels.20 This same observation was not found with transdermal HRT as the rise in CRP was found to be of metabolic origin and not secondary to an inflammatory process.9,21 Nicotine use can also increase CRP levels. Lifestyle modifications and multiple medications can reduce CRP levels. Limiting alcohol consumption and smoking cessation have been shown to reduce CRP levels.12 Weight loss and a reduction in body fat have been shown to reduce CRP levels in patients with metabolic syndrome.22 In a selected cohort from the Physician’s Health Study, the relative risk of developing a vascular event while being treated with aspirin was reduced for patients in the higher quartiles of CRP measurement.6 Clopidogrel’s effect on the reduction of CRP levels was found to be equivalent to aspirin’s in patients six months after an MI.23 Hydroxymethyl glutaryl–coenzyme A reductase inhibitors (statins), such as pravastatin and atorvastatin, have been shown to reduce CRP levels in patients in both primary and secondary cardiovascular-event prevention studies.7,–10,24,–27 Niacin, gemfibrozil, and vitamin E have been shown in limited studies to reduce CRP levels in patients with hyperlipidemia.13 Measurement of CRP levels For quantification of acute-phase reactants in cardiovascular disease, only CRP and fibrinogen have reliable and widely available laboratory assays.12 Original tests to detect CRP could only identify elevated concentrations (>8 mg/L).16 The hs-CRP assay is now commonly used to quantify CRP levels. This assay can detect CRP concentrations of <0.3 mg/L.18 The hs-CRP has become a preferred inflammatory marker to determine a patient’s cardiovascular risk, with elevated levels considered an independent risk factor for CHD.6 However, many practitioners mistakenly consider hs-CRP assay results to be part of a patient’s cholesterol assessment. The hs-CRP assay is used primarily for cardiovascular-risk assessment, whereas general CRP testing is used in the assessment of infections and chronic inflammatory diseases. CRP concentrations in these other disease states usually range from 10 to 1000 mg/L. Elevated CRP levels are also considered independent risk factors for cardiovascular disease in healthy men. In the Physician’s Health Study, CRP levels were measured by enzyme-linked immunosorbent assay in a group of otherwise healthy men who had an MI or a stroke or developed deep venous thrombosis (DVT) (n = 543).6 CRP levels were compared with those of a matched group of control patients. Patients were separated into quartiles with CRP concentrations ranging from less than 0.55 to over 2.11 mg/L after median concentrations were calculated. The differences between baseline plasma CRP concentrations of control patients versus patients who had an MI (1.10 mg/L versus 1.48 mg/L, respectively; p < 0.001) or a stroke (1.10 mg/L versus 1.30 mg/L, respectively; p < 0.003) were significant. No significant difference in CRP levels was detected between patients in the control group and patients who developed DVT. Additional data focusing on 140 men from the same study who developed symptomatic peripheral arterial disease (PAD) were matched with data for control patients.28 Levels of CRP, total cholesterol, triglycerides, and LDL cholesterol were significantly higher in patients who developed PAD compared with patients who did not. In a small study of healthy women, CRP levels were associated with cardiovascular risk.29 A sample of 122 cases of cardiovascular events was matched with a control group of healthy women in the Women’s Health Study. Twelve potential markers of cardiovascular disease or related inflammation were analyzed, including serum amyloid A, IL-6, soluble intercellular adhesion molecule type 1, lipoprotein and lipid measurements, and apolipoproteins A-I and B-100. Of the 12 markers of cardiovascular risk evaluated, only hs-CRP and the ratio of total cholesterol to high-density- lipoprotein (HDL) cholesterol independently predicted cardiovascular risk (p = 0.02). Over a three-year period, patients with low levels of hs-CRP and cholesterol had a reduced risk of death or vascular events, including MI and stroke. Women with LDL cholesterol concentrations below 130 mg/dL and increased CRP levels had a significantly greater risk of developing these study endpoints. In a full analysis of data from the Women’s Health Study, 27,939 women age 45 years or older were evaluated to define specific CRP levels and other values predictive of cardiovascular risk factors.3 Patients were followed for eight years. Study endpoints included nonfatal MI or ischemic stroke, coronary revascularization, and death from any cause. Both patients on HRT and nonusers of HRT were included. Patients were categorized into quintiles based on their CRP and LDL cholesterol levels. The quintiles for CRP ranged from 0.49 mg/L or less (lowest) to 4.19 mg/L or greater (highest). The quintiles for LDL cholesterol ranged from 97.6 mg/dL or less (lowest) to 153.9 mg/dL or greater (highest). For all study participants, an increase in event-free survival and lower relative risk of a first cardiovascular event was seen in the lower quintiles of both CRP and LDL cholesterol levels. When adjusting the quintiles for age, smoking, presence of diabetes, blood pressure, and use of HRT, the same results were observed. Given a relative risk of 1.0 for the reference quintiles in each category, the relative risk for a first cardiovascular event increased with increasing quintiles of CRP levels (1.4, 1.6, 2.0, and 2.3) and LDL cholesterol levels (0.9, 1.1, 1.3, and 1.5) (p < 0.001 for both groups). However, CRP and LDL cholesterol levels were minimally correlated (r = 0.08) (Table 11). When data were evaluated using a predictive model with C statistic and chi-square analyses, CRP appeared to be a better predictor of cardiovascular risk. Table 1. Quintiles of hs-CRP and LDL Cholesterol Established from the Women’s Health Study3,a Variable 1st Quintile (Reference Value) 2nd Quintile 3rd Quintile 4th Quintile 5th Quintile ahs-CRP = high-sensitivity C-reactive protein, LDL = low-density-lipoprotein, RR = relative risk. bAdjusted for variables of age, smoking, diabetes, hypertension, and use of hormone replacement therapy. hs-CRP (mg/L) ≤0.49 0.49 < X ≤ 1.08 1.08 < X ≤ 2.09 2.09 < X < 4.19 =4.19 RR of first cardiovascular eventb 1.0 1.4 1.6 2.0 2.3 LDL cholesterol (mg/dL) ≤97.6 97.6 < X ≤ 115.4 115.4 < X ≤ 132.2 132.2 < X < 153.9 =153.9 RR of first cardiovascular eventb 1.0 0.9 1.1 1.3 1.5 Variable 1st Quintile (Reference Value) 2nd Quintile 3rd Quintile 4th Quintile 5th Quintile ahs-CRP = high-sensitivity C-reactive protein, LDL = low-density-lipoprotein, RR = relative risk. bAdjusted for variables of age, smoking, diabetes, hypertension, and use of hormone replacement therapy. hs-CRP (mg/L) ≤0.49 0.49 < X ≤ 1.08 1.08 < X ≤ 2.09 2.09 < X < 4.19 =4.19 RR of first cardiovascular eventb 1.0 1.4 1.6 2.0 2.3 LDL cholesterol (mg/dL) ≤97.6 97.6 < X ≤ 115.4 115.4 < X ≤ 132.2 132.2 < X < 153.9 =153.9 RR of first cardiovascular eventb 1.0 0.9 1.1 1.3 1.5 Open in new tab Table 1. Quintiles of hs-CRP and LDL Cholesterol Established from the Women’s Health Study3,a Variable 1st Quintile (Reference Value) 2nd Quintile 3rd Quintile 4th Quintile 5th Quintile ahs-CRP = high-sensitivity C-reactive protein, LDL = low-density-lipoprotein, RR = relative risk. bAdjusted for variables of age, smoking, diabetes, hypertension, and use of hormone replacement therapy. hs-CRP (mg/L) ≤0.49 0.49 < X ≤ 1.08 1.08 < X ≤ 2.09 2.09 < X < 4.19 =4.19 RR of first cardiovascular eventb 1.0 1.4 1.6 2.0 2.3 LDL cholesterol (mg/dL) ≤97.6 97.6 < X ≤ 115.4 115.4 < X ≤ 132.2 132.2 < X < 153.9 =153.9 RR of first cardiovascular eventb 1.0 0.9 1.1 1.3 1.5 Variable 1st Quintile (Reference Value) 2nd Quintile 3rd Quintile 4th Quintile 5th Quintile ahs-CRP = high-sensitivity C-reactive protein, LDL = low-density-lipoprotein, RR = relative risk. bAdjusted for variables of age, smoking, diabetes, hypertension, and use of hormone replacement therapy. hs-CRP (mg/L) ≤0.49 0.49 < X ≤ 1.08 1.08 < X ≤ 2.09 2.09 < X < 4.19 =4.19 RR of first cardiovascular eventb 1.0 1.4 1.6 2.0 2.3 LDL cholesterol (mg/dL) ≤97.6 97.6 < X ≤ 115.4 115.4 < X ≤ 132.2 132.2 < X < 153.9 =153.9 RR of first cardiovascular eventb 1.0 0.9 1.1 1.3 1.5 Open in new tab Survival curves were constructed around study participants’ median CRP (1.52 mg/L) and LDL cholesterol concentrations (123.7 mg/dL), and relative risks were computed using the lowest CRP and LDL cholesterol quintiles as reference values. Relative risks for cardiovascular events were as follows: low CRP–low LDL cholesterol = 1.0, low CRP–high LDL cholesterol = 1.5, high CRP–low LDL cholesterol = 1.7, and high CRP–high LDL cholesterol = 2.4. The numbers of events per 1000 person-years were 1.2, 1.9, 3.1, and 4.5, respectively. Adjustments to Framingham scores were considered, but CRP continued to remain a strong predictor of cardiac risk and independent of LDL. Status of CRP testing AHA guidelines have established CRP as the “optional, inflammatory marker of choice” compared with other markers (e.g., serum amyloid A).12 Together, AHA and the Centers for Disease Control and Prevention (CDC) endorsed CRP testing as an additional screening mechanism for patients at intermediate to high risk for developing CHD (those with a 10–20% risk of developing CHD within the next 10 years). Since CRP is a known marker of inflammation, it is sometimes measured in patients with ACS.30 A CRP concentration exceeding 10 mg/L during an acute coronary event increases a patient’s risk of death or MI. However, if a patient’s CRP concentration continues to exceed 10 mg/L, patients should be evaluated for noncardiac sources of inflammation.12 A direct relationship between CRP level and the extent of heart muscle damage during an acute event has not been determined. Current laboratory interpretation of CRP levels is based on AHA recommendations. A common population value for hs-CRP is <10 mg/L. In general, hs-CRP concentrations of 1–3 mg/L are indicative of an average risk of cardiovascular event, but concentrations over 3 mg/L are considered a marker of greater risk. These specific levels should be considered in addition to patient-specific cardiac risk factors created by the patient’s medical history, social habits, lipid panel, and homocysteine levels. Most laboratories use commercially available test kits for hs-CRP. Patients should fast overnight before hs-CRP sample collection. Also, hs-CRP should be sampled twice (optimally two weeks apart), and the values of the two samples should be averaged.12 If the patient has an infectious disease, samples should be collected at least two weeks after the resolution of the infection to obtain an accurate baseline value to assess cardiovascular risk alone. Patients with a CRP concentration exceeding 10 mg/L should be retested, as a persistent source of inflammation or infection is likely. CRP levels and statin use in primary prevention The major primary prevention study that analyzed CRP data was the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).31,32 The goal of this randomized, double-blind, placebo-controlled trial was to evaluate CRP levels in 5742 patients with either average total and LDL cholesterol levels or below-average HDL cholesterol levels. Study participants included men or postmenopausal women age 45–73 years who did not have a history of uncontrolled hypertension, insulin-dependent diabetes, or secondary hyperlipidemia or were 150% of their ideal body mass index based on their height. The median LDL cholesterol level and total cholesterol:HDL cholesterol ratio were 149.1 mg/dL and 5.96, respectively. The median CRP was 0.16 mg/L. Patients were randomized to receive either placebo or lovastatin 20 mg daily for a 12-week run-in period, where they followed a Step I (low saturated fat, low cholesterol) diet. Lovastatin was increased to 40 mg at three months if the patient’s LDL cholesterol concentration exceeded 110 mg/dL. Patients were followed for 5.2 years. Patients’ CRP and LDL levels were divided into four quartiles (Table 22). The primary endpoint was the occurrence of the first acute major coronary event (i.e., fatal or non-fatal MI, unstable angina, or sudden death from cardiac causes). Table 2. Quartiles of CRP and LDL Cholesterol Established from Primary Prevention Study (AFCAPS/TexCAPS) with Statins31,a Variable 1st Quartile (n= 1448) 2nd Quartile (n= 1428) 3rd Quartile (n= 1420) 4th Quartile (n= 1446) aCRP = C-reactive protein, LDL = low-density-lipoprotein, AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study. LDL cholesterol (mg/dL) ≤149.1 ≤149.1 >149.1 >149.1 CRP (mg/L) ≤0.16 >0.16 ≤0.16 >0.16 Variable 1st Quartile (n= 1448) 2nd Quartile (n= 1428) 3rd Quartile (n= 1420) 4th Quartile (n= 1446) aCRP = C-reactive protein, LDL = low-density-lipoprotein, AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study. LDL cholesterol (mg/dL) ≤149.1 ≤149.1 >149.1 >149.1 CRP (mg/L) ≤0.16 >0.16 ≤0.16 >0.16 Open in new tab Table 2. Quartiles of CRP and LDL Cholesterol Established from Primary Prevention Study (AFCAPS/TexCAPS) with Statins31,a Variable 1st Quartile (n= 1448) 2nd Quartile (n= 1428) 3rd Quartile (n= 1420) 4th Quartile (n= 1446) aCRP = C-reactive protein, LDL = low-density-lipoprotein, AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study. LDL cholesterol (mg/dL) ≤149.1 ≤149.1 >149.1 >149.1 CRP (mg/L) ≤0.16 >0.16 ≤0.16 >0.16 Variable 1st Quartile (n= 1448) 2nd Quartile (n= 1428) 3rd Quartile (n= 1420) 4th Quartile (n= 1446) aCRP = C-reactive protein, LDL = low-density-lipoprotein, AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study. LDL cholesterol (mg/dL) ≤149.1 ≤149.1 >149.1 >149.1 CRP (mg/L) ≤0.16 >0.16 ≤0.16 >0.16 Open in new tab Compared with placebo, lovastatin was associated with a 37% reduction in combined primary endpoints (p < 0.001) and a 14.8% reduction in CRP level (p < 0.001).31,32 A direct relationship between LDL cholesterol and CRP levels was not established, and change in lipid values was not associated with a change in CRP levels. With increasing quartiles, the relative risk of having a coronary event decreased significantly among patients receiving lovastatin versus placebo (p < 0.01). The original analysis found a 21% increase in risk for each escalating quartile. When the analysis was adjusted for age, sex, smoking status, hypertension, and family history, a 17% increase in risk was found with each quartile increase (p = 0.01). Lovastatin reduced the risk of events in all patients with LDL cholesterol levels higher than the median, regardless of CRP levels (p < 0.001). This reduction in risk with lovastatin was also seen in patients with CRP levels above the median and LDL cholesterol concentrations of ≤149.1 mg/dL (p < 0.04). Such a reduction in risk of cardiovascular events with lovastatin was not observed in patients with LDL cholesterol and CRP levels below median values. After examining results from this study, some researchers have inferred that the cardiovascular risk for patients with high CRP and low LDL cholesterol levels may be about the same as the risk for patients with high LDL cholesterol and low CRP levels.33 A small study was conducted in a Texas hyperlipidemia clinic to determine if statins other than lovastatin would lower CRP levels.24 Study participants included patients age 18–70 years with LDL cholesterol concentrations of >130 mg/dL and triglyceride concentrations of 200–600 mg/dL (n = 22). Patients were treated with simvastatin 20 mg, atorvastatin 10 mg, or pravastatin 40 mg daily. Levels of hs-CRP and LDL cholesterol decreased significantly with all three statins (p < 0.025). A decrease in triglyceride levels was seen with simvastatin and atorvastatin only (p < 0.001 compared with baseline). This 12-week study did not measure cardiovascular endpoints, but the results may support the antiinflammatory effect of the statins. The results of the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial are eagerly anticipated.34 JUPITER is being conducted to determine whether rosuvastatin 20 mg p.o. will reduce the risk of major cardiovascular events in patients with low LDL cholesterol concentrations (<130 mg/dL) who are at high vascular risk and have hs-CRP concentrations of ≥2 mg/L. Additional information to be evaluated in this study is the effect of rosuvastatin on the rate of diabetes mellitus and on the inflammatory process. CRP levels and statin use for secondary prevention The success seen with statins in primary cardiovascular risk reduction led to the evaluation of statins in patients with existing cardiovascular disease. The Cholesterol and Recurrent Events (CARE) study found that cholesterol-lowering therapy was beneficial in most patients with coronary disease who had average cholesterol levels.25 The CARE study included 4159 patients who had a history of MI and total cholesterol concentrations of <240 mg/dL (mean ± S.D., 209 ± 17 mg/dL) and LDL cholesterol concentrations of 115–174 mg/dL (mean ± S.D., 139 ± 15 mg/dL). Patients received either 40 mg of pravastatin daily or placebo. The primary outcome measure of a fatal coronary event or a nonfatal MI occurred in 10.2% of the pravastatin-treated group and 13.2% of patients in the placebo group. Patients receiving pravastatin had a 24% lower risk of the primary endpoint compared with patients in the placebo group (95% confidence interval [CI], 9–36; p = 0.003). A significantly greater incidence of coronary artery bypass graft (CABG) surgery and angioplasty was seen in patients receiving placebo (p < 0.05). Pravastatin versus placebo The conclusions of the CARE study were further explored by Ridker et al.7 to evaluate whether CRP and serum amyloid A levels were associated with recurrent coronary events. Prerandomization blood samples were evaluated from 391 patients enrolled in the CARE study who suffered recurrent nonfatal MI or a fatal coronary event. These samples were matched in a nested, case-controlled fashion with patients who did not have a second vascular event. Of note, it was not designated as to whether or not they received pravastatin or placebo. The serum levels of both inflammatory markers were higher in patients with recurrent events than in patients without recurrent events. However, the difference between the two groups was not considered significant (p ≥ 0.05). Patients in the highest CRP quintile (>0.66 mg/L) had a 75% higher relative risk of cardiovascular events than patients in the lowest CRP quintile (<0.12 mg/L) (p = 0.02). Ridker et al.7 also evaluated 708 participants from the CARE study who had CRP and serum amyloid A values above or below the 90th percentile (CRP concentration of >0.99 mg/L). Patients with CRP levels exceeding the 90th percentile were classified as having inflammation, and those with CRP levels below the 90th percentile were considered to be without inflammation. These groups were further divided by whether they received pravastatin. Regardless of inflammation status, patients in the pravastatin-treatment group had a 28% reduced risk of recurrent MI or coronary death compared with patients in the placebo group (p = 0.03). Among patients with inflammation, pravastatin prevented twice as many coronary events than did placebo (54% versus 25%, respectively). The authors concluded that there was an association between pravastatin’s ability to reduce inflammation and prevent recurrent coronary events. To examine the long-term effects of pravastatin on CRP levels, Ridker et al.8 selected the 477 participants in the CARE study who remained free of recurrent cardiovascular events and had available five-year blood samples. It was noted that CRP levels continued to increase in patients who received placebo but decreased in patients treated with pravastatin. Since these results were adjusted for several factors, including lipid levels, the investigators concluded that the reduction seen in CRP levels in the pravastatin-treated group was related to the nonantihyperlipidemic effects of the drug. Pravastatin versus atorvastatin Cannon et al.10 conducted a randomized, double-blind, double-dummy trial to compare the degree of LDL cholesterol lowering with 40 mg of pravastatin (moderate therapy) versus 80 mg of atorvastatin (intensive therapy). This study, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22), included 4162 patients who had been hospitalized for ACS within the 10 days preceding study enrollment. Study participants had a total cholesterol level of ≤240 mg/dL within 24 hours of enrollment or as an outpatient within the previous six months or had a total cholesterol concentration of ≤200 mg/dL with lipid-lowering therapy. The primary outcome measure was the time from randomization until the first occurrence of one of the following events: death from any cause, MI, documented unstable angina, hospitalization, revascularization with either percutaneous coronary intervention or CABG surgery (performed at least 30 days after study randomization), or stroke. The primary outcome measure occurred in 26.3% of patients receiving moderate therapy and 22.4% of patients receiving intensive therapy (p = 0.0005). The median LDL cholesterol levels reached in the moderate and intensive therapy groups were 96 and 62 mg/dL, respectively (p < 0.001). The median baseline CRP level in both the pravastatin and atorvastatin groups dropped from 12.3 to 2.1 mg/L (in the pravastatin group) and to 1.3 mg/L (in the atorvastatin group) by the end of the study (p < 0.001). The authors concluded that intensive statin therapy with atorvastatin 80 mg was more effective in protecting against death or major cardiovascular events than moderate therapy with pravastatin 40 mg. Ridker and colleagues9 conducted a study that included 3745 patients from the PROVE IT-TIMI 22 trial. The patients selected had to be free of recurrent events and have 30-day follow-up laboratory data. Both LDL cholesterol and CRP levels were reduced by statin therapy at 30 days, and only a small correlation was found between the achieved LDL cholesterol and CRP values (r = 0.16, p = 0.001). A similar level of correlation was observed in patients with subsequent recurrent coronary events (r = 0.18, p = 0.004). Less than 3% of the variance in achieved CRP levels was explained by the variance in achieved LDL cholesterol level. Patients in whom statin therapy resulted in LDL cholesterol levels of <70 mg/dL had lower age-adjusted rates of recurrent MI or death from coronary causes (2.7 versus 4.0 events per 100 person-years, p = 0.008), and patients with a CRP concentration of <2 mg/L had 2.8 versus 3.9 events per 100 person-years (p = 0.006). Data were separated into quartiles based on achievement of the LDL cholesterol or CRP goal (Table 33). It was concluded that, regardless if goal LDL cholesterol (<70 mg/dL) was achieved, patients with low CRP levels after statin therapy may have better clinical outcomes, compared with patients with higher CRP levels. Over 80% of patients who achieved optimum targets were receiving atorvastatin 80 mg. No difference regarding clinical endpoints was seen between treatment with atorvastatin 80 mg and pravastatin 40 mg once patients met LDL cholesterol and CRP targets. Table 3. Age-Adjusted Rates of Endpoints in PROVE IT-TIMI 22 According to LDL Cholesterol or CRP Level9,a Subgroup (LDL Cholestorol Conc., CRP Conc.) n No. Person- Years No. Recurrent Events Age-Adjustment Event Rate/ 100 Person- Years aPROVE IT-TIMI 22 = Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22, LDL = low-density-lipoprotein, CRP = C-reactive protein. ≥70 mg/dL, ≥2 mg/L 1086 2086.2 92 4.6 <70 mg/dL, ≥2 mg/L 742 1473.0 47 3.1 ≥70 mg/dL, <2 mg/L 899 1764.5 56 3.2 <70 mg/dL, <2 mg/L 1018 2038.4 48 2.4 Subgroup (LDL Cholestorol Conc., CRP Conc.) n No. Person- Years No. Recurrent Events Age-Adjustment Event Rate/ 100 Person- Years aPROVE IT-TIMI 22 = Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22, LDL = low-density-lipoprotein, CRP = C-reactive protein. ≥70 mg/dL, ≥2 mg/L 1086 2086.2 92 4.6 <70 mg/dL, ≥2 mg/L 742 1473.0 47 3.1 ≥70 mg/dL, <2 mg/L 899 1764.5 56 3.2 <70 mg/dL, <2 mg/L 1018 2038.4 48 2.4 Open in new tab Table 3. Age-Adjusted Rates of Endpoints in PROVE IT-TIMI 22 According to LDL Cholesterol or CRP Level9,a Subgroup (LDL Cholestorol Conc., CRP Conc.) n No. Person- Years No. Recurrent Events Age-Adjustment Event Rate/ 100 Person- Years aPROVE IT-TIMI 22 = Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22, LDL = low-density-lipoprotein, CRP = C-reactive protein. ≥70 mg/dL, ≥2 mg/L 1086 2086.2 92 4.6 <70 mg/dL, ≥2 mg/L 742 1473.0 47 3.1 ≥70 mg/dL, <2 mg/L 899 1764.5 56 3.2 <70 mg/dL, <2 mg/L 1018 2038.4 48 2.4 Subgroup (LDL Cholestorol Conc., CRP Conc.) n No. Person- Years No. Recurrent Events Age-Adjustment Event Rate/ 100 Person- Years aPROVE IT-TIMI 22 = Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22, LDL = low-density-lipoprotein, CRP = C-reactive protein. ≥70 mg/dL, ≥2 mg/L 1086 2086.2 92 4.6 <70 mg/dL, ≥2 mg/L 742 1473.0 47 3.1 ≥70 mg/dL, <2 mg/L 899 1764.5 56 3.2 <70 mg/dL, <2 mg/L 1018 2038.4 48 2.4 Open in new tab The benefit of statin use in the secondary prevention of fatal and nonfatal coronary events has been shown, but few studies have examined the effects of statin use in physical atherosclerosis. Nissen et al.26 randomized 654 patients to receive moderate therapy (pravastatin 40 mg daily) or intensive therapy (atorvastatin 80 mg daily). A total of 502 patients had evaluable intravascular ultrasound examinations. The primary outcome measure was the percentage of change in atheroma volume compared with baseline. The results showed that the progression rate was lower in the atorvastatin group (–0.4%; 95% CI, −2.35% to 1.49%) compared with the pravastatin group (2.7%; 95% CI, 0.24–4.67%). There was also benefit in the atorvastatin group regarding the change in total atheroma volume (p = 0.02) and the percentage atheroma volume (p < 0.001). The authors found a significant benefit in intensive therapy compared with moderate therapy in the reduction of progression of coronary atherosclerosis. In the 502 patients with evaluable ultrasounds, Nissen et al.27 further examined the relationship between the reductions in LDL cholesterol and CRP levels and the rate of disease progression measured by ultrasonagraphy. In this evaluation, they found a slower rate of progression in the intensive therapy group compared with patients receiving moderate therapy (p = 0.001). However, a weak but significant correlation between the percent reductions in LDL cholesterol and CRP levels was found (r = 0.13, p = 0.005). There was not a significant correlation in the individual pravastatin- and atorvastatin-treatment groups. Discussion Since the 2003 article published by Pearson et al.,12 CRP levels have been partially considered in the general assessment of cardiac risk but not necessarily taken into consideration when monitoring a patient’s pharma-cotherapy. For primary prevention of cardiovascular events, evaluating CRP levels in patients with average or below-average cholesterol levels may be of benefit in limited clinical circumstances. In AFCAPS/TexCAPS, with the exception of the group with LDL cholesterol and CRP levels less than the median values, the number needed to treat in each quartile to derive a risk-reduction benefit varied widely (range, 35–86 patients). In addition, patients who were being considered for statin therapy for the treatment of other disease states (e.g., insulin-dependent diabetes, uncontrolled hypertension, secondary hyperlipidemia, body mass index greater than 50% of desirable) were excluded from the study, and 20% of patients enrolled were taking aspirin, a drug known to reduce CRP levels. Currently, measuring hs-CRP may not be a useful intervention if patients already need statin therapy when evaluated by guidelines such as those available from the NCEP. The NCEP recommends statin therapy for patients with an LDL concentration of ≥ 130 mg/dL and for patients with LDL cholesterol concentrations of 100–129 mg/dL who have excessive risk factors.11,22 Clinicians are also likely to initiate aggressive statin therapy in very-high-risk patients, including those with CHD risk equivalents. Along with the recommendations from the NCEP, results of current secondary prevention studies suggest that CRP testing would not add much to the clinical management of a patient already receiving statin therapy. In the CARE trial, pravastatin was found to reduce CRP levels, which appeared to be unrelated to the decrease in LDL cholesterol levels, further confirming the status of CRP as an independent marker of cardiovascular risk. However, when compared with placebo, all pravastatin-treated patients had a significant reduction in coronary events, regardless of their CRP level. Given this fact, it may be unnecessary to check the CRP level before initiating therapy with moderate-dosage statins. Data from the PROVE IT-TIMI 22 study suggest the same regarding moderate and intensive statin therapy. Atorvastatin 80 mg led to significantly decreased CRP and LDL cholesterol levels at 30 days compared with pravastatin 40 mg, but all of the data in this study were measured in age-adjusted event rate per 100 person-years. Though significant, the difference between the groups that achieved an LDL cholesterol concentration of <70 mg/dL and had a CRP value of ≤2 mg/L versus those with an LDL cholesterol concentration of 70 mg/dL or less and a CRP value of less than 2 mg/L was 3.1 versus 2.4 per person-years. Finally, once goal CRP and LDL cholesterol levels were achieved in study patients, little evidence showed that either atorvastatin or pravastatin was superior in improving clinical outcomes. 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TI - Impact of C-reactive protein on treatment of patients with cardiovascular disease
JO - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp060542
DA - 2007-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/impact-of-c-reactive-protein-on-treatment-of-patients-with-1DCjL7vAtM
SP - 2009
VL - 64
IS - 19
DP - DeepDyve
ER -