Comparison of Effects of High (80 mg) Versus Low (20 mg) Dose of Simvastatin

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1 Comparison of Effects of High (80 mg) Versus Low (20 mg) Dose of Simvastatin on C-Reactive Protein and Lipoproteins in Patients With Angiographic Evidence of Coronary Arterial Narrowing Kent G. Meredith, MD a,b, Benjamin D. Horne, PhD, MPH a, Robert R. Pearson, BS a, Chloe Allen Maycock, MD a, Donald L. Lappe, MD a, Jeffrey L. Anderson, MD a,b, and Joseph B. Muhlestein, MD a,b, * Although previous studies have demonstrated that various statins decrease levels of high-sensitivity C-reactive protein (hs-crp), the dose-response relation for lowering hs- CRP by the clinically important drug simvastatin compared with lipid lowering is unclear. A 16-week, randomized, double-blind study was performed in patients with stable coronary artery disease and high hs-crp levels (>3 mg/l). Subjects were randomized to placebo, 20 mg of simvastatin, or 80 mg of simvastatin for 12 weeks. Those currently on a statin first underwent a 4-week washout. Of the 107 total patients randomized, 96 completed the trial, and 89 were able to be evaluated for efficacy. Changes in hs-crp differed across simvastatin and placebo groups (change score 1.6 vs 0.6 mg/l, p 0.004), but no dose response was observed when comparing 80 with 20 mg/day ( 0.6 vs 0.5 mg/l, respectively). A strong dose response was observed for changes in total (p <0.01) and low-density lipoprotein (p <0.001) cholesterol. hs-crp changes did not correlate with low-density lipoprotein changes. In conclusion, this randomized trial in patients with chronic stable coronary artery disease showed a strong dose response for simvastatin for total and low-density lipoprotein cholesterol lowering but not for hs-crp Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99: ) The recognition of statin benefits beyond lipid lowering has prompted significant debate regarding the extent to which the cardiovascular benefit is derived from lipoprotein modification compared with nonlipid pleiotropic effects. 1 3 Further, the nature of this interaction between lipid effects and anti-inflammatory effects is not well understood, and there is a clear need for further pharmacologic studies of the nonlipid statin effects in relation to dose intensity. The Effects of Simvastatin on C-reactive Protein (ESP) trial was designed to determine if a dose response exists for highsensitivity C-reactive protein (hs-crp) lowering within the usual therapeutic range for simvastatin and to see whether it differs from that of low-density lipoprotein (LDL) and total cholesterol lowering. Methods Study objectives: The primary objective of the ESP trial was to assess the dose response for hs-crp lowering by simvastatin within the usual therapeutic dose range in stable patients with chronic coronary artery disease (CAD). The a Cardiovascular Department, LDS Hospital, and the b Department of Medicine, Division of Cardiology, University of Utah, Salt Lake City, Utah. Manuscript received March 2, 2006; revised manuscript received and accepted July 25, This investigator-initiated trial was funded by an unrestricted grant from Merck & Co., Inc., Whitehouse Station, New Jersey. *Corresponding author: Tel: ; fax: address: brent.muhlestein@intermountainmail.org (J.B. Muhlestein). secondary objective was to determine the degree of correlation between treatment-related changes in hs-crp and LDL (and total) cholesterol. Study design and population: The ESP trial was a randomized, double-blind, parallel study of 2 doses of simvastatin (Merck & Co., Inc., Whitehouse Station, New Jersey) and placebo (Figure 1). The daily dosing regimens were 20 mg of simvastatin, 80 mg of simvastatin, and placebo. Randomization to these regimens occurred in a ratio of 2:2:1, respectively. Subjects were selected who had undergone elective coronary angiography, were found to have evidence of stable but discernible CAD, and had a baseline hs-crp that was 3 mg/l. This level has been associated with increased cardiovascular risk. 4 Subjects were excluded if they had been hospitalized within 90 days with an acute coronary syndrome, if they had undergone a coronary revascularization procedure within 90 days, or if they had a known acute or long-term inflammatory process. No enrollment criteria regarding baseline lipid levels were employed. The protocol was in accordance with Declaration of Helsinki standards and was approved by the facility s institutional review board. All subjects gave written informed consent before study entry. Subjects whose history and angiographic findings qualified them for the study had blood drawn for hs-crp, lipid levels, and liver function tests; those with a hs-crp level 3 mg/l were enrolled. Before beginning blinded therapy, subjects already on a statin first underwent a 4-week washout period followed by resampling of blood for hs-crp and /07/$ see front matter 2007 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 150 The American Journal of Cardiology ( Figure 1. In the ESP trial design, patients previously on statin therapy underwent a 4-week washout before randomization. *History, physical examination, hs-crp, lipid panel, and blood chemistry including liver function. **History, physical examination, hs-crp, and lipid panel. Simva simvastatin. Table 1 Baseline characteristics of study subjects Variable Placebo 20 mg Simvastatin 80 mg Simvastatin p Value (n 24) (n 37) (n 35) Age (yrs) Men 15 (62%) 24 (65%) 25 (71%) 0.77 Hypertension 14 (58%) 27 (73%) 17 (48%) 0.20 Dyslipidemia 16 (67%) 23 (62%) 20 (57%) 0.73 Diabetes mellitus 4 (17%) 9 (24%) 4 (11%) 0.36 Smoking 5 (21%) 12 (32%) 7 (20%) 0.49 Previous statin use 15 (63%) 19 (51%) 20 (57%) 0.75 Previous myocardial infarction 6 (25%) 8 (22%) 7 (20%) 0.93 Previous revascularization 8 (33%) 10 (27%) 10 (29%) 0.92 CAD vessels involved 0 9% 28% 24% % 38% 29% 2 15% 12% 29% 3 21% 22% 19% CAD stenosis severity Luminal irregularity 9% 28% 24% 0.15 Mild 10% 39% 9% 9% 24% Moderate 40% 69% 21% 19% 5% Severe 70% 100% 62% 44% 48% Ejection fraction (%) CRP (mg/l) 4.5 (0.8 48) 5.2 ( ) 5.1 (0.6 33) 0.53 Total cholesterol mg/dl mmol/l Triglycerides mg/dl 140 (48 319) 187 (28 1,243) 141 (57 547) 0.07 mmol/l units 1.6 ( ) 2.1 (0.3 14) 1.6 ( ) HDL cholesterol mg/dl mmol/l units LDL cholesterol mg/dl mmol/l Values are means SDs, numbers of patients (percentages), or medians (ranges). HDL high-density lipoprotein.

3 Coronary Artery Disease/The ESP Trial 151 Figure 2. Change in hs-crp for each treatment group after 12 weeks; p for 20 mg/day of simvastatin (Simva 20) plus 80 mg/day of simvastatin (Simva 80). Figure 3. Change in LDL cholesterol for each treatment group at 12 weeks; p for test of trend. Abbreviations as in Figure 2. fasting lipids, which served as their study baseline. Requalification of hs-crp was not required after washout. After enrollment, patients were randomized to blinded therapy with placebo, 20 mg/day of simvastatin, or 80 mg/day of simvastatin. After randomization, patients received their assigned study medication for 12 weeks. Follow-up visits were at 2, 4, 8, and 12 weeks. At each visit, an interval medical history was obtained, focusing on cardiovascular events, potential adverse effects, and current medications. A physical examination was also performed. Laboratory testing: At each visit, fasting venous blood was sampled for hs-crp and lipid levels. Aspartate aminotransferase and alanine aminotransferase levels were determined at 2 and 12 weeks. The hs-crp level was determined by an assay from Dade-Behring (Deerfield, Illinois). 5 Statistical analysis: The primary comparison of this trial was the dose-related change in hs-crp at 12 weeks versus baseline among placebo and 20- and 80-mg simvastatin groups. Nonparametric (Mann-Whitney) testing was used to assess differences in change scores. In case of missing or invalid values at 12 weeks for hs-crp or lipid measurements, the 8-week result was carried forward. For variables with non-normal distributions, median rather than mean values are reported. The secondary comparison of interest was the correlation between changes in LDL and total cholesterol and hs-crp levels with simvastatin therapy. Correlations were assessed using Spearman s coefficients. Enrollment of 107 patients was designed to provide 95% power at a significance ( ) level of 0.05 to detect a 20% difference in hs-crp levels with 20 mg of simvastatin compared with placebo therapy. This would allow 90% to 95% power to detect an additional 10% decrease in hs-crp with 80 versus 20 mg of simvastatin. Results Characteristics of study population: In total, 253 consenting patients were initially screened; 121 met hs-crp and other inclusion criteria, and 107 patients agreed to Figure 4. Change in total cholesterol (TC) for each treatment group at 12 weeks; p for test of trend. Other abbreviations as in Figure 2. continue in the study and were randomized to drug therapy. Of these, 96 completed the statin washout (if needed) and the 12-week treatment period, and 89 had analyzable datasets. (Fourteen withdrew consent early after randomization for reasons including concerns for perceived placebo therapy, unwillingness to maintain the follow-up schedule, and so forth). Baseline characteristics of the 89 evaluated subjects are presented in Table 1. Treatment-related changes in hs-crp: The primary study analysis was the change in hs-crp by drug dose (Figure 2). At 12 weeks, hs-crp was significantly and similarly lower with 20 mg/day (median change 0.5 mg/l) and 80 mg/day ( 0.6 mg/l) of simvastatin than with placebo (which increased by a median of 1.6 mg/l). Also of note was the substantial intersubject variability in response, as evidenced by broad confidence intervals (Figure 2). The hs-crp response differed by treatment group with a p value of For pairwise comparisons, the 20-mg simvastatin response differed significantly from that of placebo ( 0.5 vs 1.6 mg/l, p 0.004). Similarly, the 80-mg simvastatin response differed from that of placebo ( 0.6 vs 1.6 mg/l,

4 152 The American Journal of Cardiology ( Table 2 Change scores for any simvastatin versus placebo Variable Placebo 20/80 mg Simvastatin p Value CRP (mg/l) ( 1.7 to 20) 0.6 ( 26 to 24) Total cholesterol (mg/dl) 3 ( 58 to 77) 57 ( 182 to 34) Triglycerides (mg/dl) 5( 93 to 132) 32 ( 359 to 192) HDL cholesterol (mg/dl) 3.0 ( 7.0 to 18) 1.0 ( 35 to 51) LDL cholesterol (mg/dl) 5 ( 63 to 57) 43 ( 195 to 55) Values are mean change scores and medians (ranges). Abbreviation as in Table 1. Table 3 Correlation of change scores Variable CRP TC LDL HDL TG CRP 1.0 TC LDL HDL TG TC total cholesterol; TG triglycerides; other abbreviation as in Table 1. p 0.025). However, there was no difference in response between the 20- and 80-mg simvastatin regimens (p 0.82). Thus, no dose response was observed for hs-crp within the commonly used clinical dose range for simvastatin of 20 to 80 mg/day for this stable cohort of patients with CAD. Change scores in lipid and lipoprotein fractions by treatment: In contrast to hs-crp response, a strong doseresponse relation was observed for LDL cholesterol, with a p value for the test of trend by dose (Figure 3). Median LDL cholesterol change scores were 3.6, 31, and 61 mg/dl for placebo, 20 mg of simvastatin, and 80 mg of simvastatin, respectively. A similar dose response was observed for total cholesterol (p 0.001; Figure 4). Median total cholesterol change scores were 1.3, 45, and 72.9 mg/dl for placebo, 20 mg of simvastatin, and 80 mg of simvastatin, respectively. Overall and pairwise statistical testing showed that these responses differed markedly across treatment groups, with p values For pairwise comparisons, 20 mg of simvastatin differed from placebo for LDL and total cholesterol, with decreases of 40 to 42 compared with 4 mg/dl (p 0.001). Simvastatin at 80 mg/day lowered LDL and total cholesterol by 66 to 70 mg/dl, which was not only highly significant compared with placebo (p 0.001) but also differed from simvastatin at 20 mg/day (p 0.003), thus confirming the expected dose-related response within this range. When 20 and 80 mg/day were combined (Table 2), these results were strengthened. In contrast to LDL and total cholesterol, no dose response was observed for high-density lipoprotein cholesterol or triglycerides. Figure 5. Absence of correlation between hs-crp lowering and lipid lowering. Table 3 presents results for the secondary end point, i.e., correlation between changes in hs-crp and changes in LDL and total cholesterol. Although hs-crp and LDL (and total) cholesterol measurements were decreased by simvastatin compared with placebo, there was essentially no correlation between individual responses to hs-crp versus lipid lowering. Spearman s correlation coefficients were only 0.09 (p 0.44) for change in hs-crp compared with change in LDL cholesterol and 0.13 (p 0.23) for change in hs-crp compared with change in total cholesterol. In contrast, changes in total and LDL cholesterol were highly correlated, as expected, with a correlation coefficient of 0.91 (p 0.001). Figure 5 shows the lack of correlation in individual responses of hs-crp and LDL cholesterol. Discussion Previous statin trials have established hs-crp lowering of lesser or greater magnitude, depending on which statin and dose was used and the patient population tested However, previous randomized, controlled trials have not adequately addressed the question of the dose response for hs-crp lowering for commonly used statins compared with lipids in stable patients with CAD. The ESP trial importantly adds to current understanding by showing that, in stable patients with long-term disease, anti-inflammatory activity as reflected by hs-crp lowering is well established at a moderate dosage for 1 of the most widely used drugs in the class, simvastatin, and is not measurably augmented further at high dose. Recent studies have provided additional insight into differential dose-response relations of hs-crp lowering to statins. Among the most notable, the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) 11,12 study and the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) 13 trial compared moderate- with high-intensity therapy, although this was done by comparing 2 different statins. The 2 trials showed significantly greater hs-crp lowering in the intensive treatment group.

5 Coronary Artery Disease/The ESP Trial 153 PROVE IT compared 80 mg/day of atorvastatin with 40 mg/day of pravastatin in unstable patients with an acute coronary syndrome and showed decreases in hs-crp at 30 days (30%) and 4 months (38%) in the intensive treatment arm. Levels of hs-crp at 4 months in either treatment arm were identical to end-of-study levels (mean follow-up 24 months), suggesting no further decrease in hs-crp beyond the initial response. The REVERSAL trial was smaller (n 502), but compared the same treatment protocol as PROVE IT (atorvastatin vs pravastatin) in stable patients with CAD, similar to those in the ESP trial. Mean hs-crp was significantly lower with high-intensity treatment after 18 months (1.8 vs 2.9 mg/l, p 0.001). Interestingly, the change in geometric mean hs-crp in the pravastatin group after 18 months was 0.2 mg/l (interquartile range 1.5 to 1.6), suggesting little or no long-term decrease from pravastatin. In contrast, the Pravastatin Inflammation/CRP Evaluation (PRINCE) trial did show a significant, although modest, decrease over 24 weeks with pravastatin. 8 Aside from the ESP trial, the only published trial to date of differential dosing with the same agent, simvastatin, is Phase Z of the A to Z Trial, which compared low (20 mg/day) with high (80 mg/day) doses after a lead-in period with 4,497 patients. 14 Unlike patients in the ESP trial, those in the A to Z Trial were unstable with acute coronary syndromes. Although the follow-up time in the A to Z Trial was 8 months, the low-dose arm was actually on placebo for the first 4 months; therefore, the actual comparison period consisted of only 4 months. Like the ESP trial, a significant decrease in hs-crp was seen with low (from 20.4 to 1.8 mg/l) and high (from 20.1 to 1.5 mg/l) doses. Although the absolute difference in hs-crp at 8 months in low- versus high-dose arms was modest (0.3 mg/l, or 16%), this difference was significant (p 0.001), in contrast to the ESP trial. A conceivable hypothesis for the difference may lie in the potential for greater hs-crp lowering in the unstable patients with acute coronary syndrome of the A to Z Trial compared with the stable patients with long-term disease in the ESP trial, although clearly a definitive explanation must await future trials designed for this purpose. The ongoing Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, comparing 80 with 20 mg of simvastatin in high-risk, stable patients, will likely provide significant insight into this debate. 15 A significant limitation of the ESP trial is that only a single statin was tested. Further, the study tested only 2 dose levels, a beginning or low-intensity dose and a high-intensity dose; therefore, no information can be gained regarding the minimum threshold for hs-crp lowering. The relatively short duration of the ESP trial may have prevented discovery of a delayed dose response in hs-crp lowering from high-intensity treatment. This possibility is underscored by the fact that a modest difference was seen with longer follow-up in the high-intensity group of the A to Z Trial. Moreover, this trial was relatively small, although it did achieve the prespecified level of the primary end point. 1. Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation 2004;109(suppl):II-18 II Yeh ET. CRP as a mediator of disease. Circulation 2004;109(suppl): II-11 II Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. 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