Figure 1. Figure 1. Relationship between LDL Cholesterol and CRP Levels Achieved after 30 Days of Statin Therapy. Overall, less than 3 percent of the variation in achieved CRP levels was explained by the variation in achieved LDL cholesterol levels (r=0.16, P=0.001). To convert values for cholesterol to millimoles per liter, multiply by 0.02586.

The mean age of the 3745 participants at study entry was 58 years, and 22 percent were women. Forty-nine percent had a history of hypertension, 17 percent had diabetes, and 36 percent were current smokers. Although the levels of both LDL cholesterol and CRP were reduced by statin therapy at 30 days, the correlation between the achieved values was small (r=0.16, P=0.001), so that less than 3 percent of the variance in achieved CRP levels was explained by the variance in achieved LDL cholesterol levels (Figure 1). This minimal level of correlation was also observed in the subgroup of patients who subsequently had recurrent coronary events (r=0.18, P=0.004).

Table 1. Table 1. Relative Risk of Recurrent Coronary Events after Statin Therapy, According to the Quartile of LDL Cholesterol and CRP Levels Achieved.

There was a linear relationship between the levels of LDL cholesterol achieved after statin therapy and the risk of recurrent myocardial infarction or death from coronary causes. Fully adjusted relative risks for those in the second lowest, second highest, and highest quartiles of achieved LDL cholesterol level, as compared with those in the lowest quartile (the reference group) were 1.1 (P=0.80), 1.2 (P=0.30), and 1.7 (P=0.006), respectively (Table 1). However, despite the almost complete independence of achieved CRP and achieved LDL cholesterol levels, there was also a linear relationship between the levels of CRP achieved after statin therapy and the risk of recurrent myocardial infarction or death from coronary causes, so that fully adjusted relative risks for those in the second lowest, second highest, and highest quartiles of achieved CRP level, as compared with those in the lowest quartile of achieved CRP level (the reference group), were 1.5 (P=0.06), 1.3 (P=0.15), and 1.7 (P=0.01). Additional adjustment for concomitant cardiovascular medications had no effect on these estimates.

Table 2. Table 2. Age-Adjusted Rates of Recurrent Myocardial Infarction or Death from Coronary Causes, According to the LDL Cholesterol and CRP Level Achieved by Statin Therapy.

Figure 2. Figure 2. Cumulative Incidence of Recurrent Myocardial Infarction or Death from Coronary Causes, According to Whether the Achieved LDL Cholesterol or CRP Levels Were above or below the Median. The approximate median value of LDL cholesterol was 70 mg per deciliter (1.8 mmol per liter), and the median value of CRP was 2 mg per liter. The median value of each marker is included for the sake of completeness, since no patient had the exact median value of either marker.

Age-adjusted rates of recurrent myocardial infarction or death from coronary causes are shown in Table 2 according to whether the level of LDL cholesterol achieved was greater than or less than 70 mg per deciliter and whether the level of CRP achieved was greater than or less than 2 mg per liter. Patients in whom statin therapy resulted in LDL cholesterol levels of less than 70 mg per deciliter had lower age-adjusted rates of recurrent myocardial infarction or death from coronary causes than did patients in whom statin therapy did not achieve this goal (2.7 vs. 4.0 events per 100 person-years, P=0.008) (Table 2 and Figure 2). However, despite the minimal correlation between achieved LDL cholesterol and CRP levels, a virtually identical difference in the age-adjusted rates of events was also observed among patients in whom statin therapy resulted in CRP levels of less than 2 mg per liter as compared with those in whom statin therapy resulted in higher CRP values (2.8 vs. 3.9 events per 100 person-years, P=0.006) (Table 2 and Figure 2).

Figure 3. Figure 3. Cumulative Incidence of Recurrent Myocardial Infarction or Death from Coronary Causes, According to the Achieved Levels of Both LDL Cholesterol and CRP. The median value of each marker is included for the sake of completeness, since no patient had the exact median value of either marker.

As also shown in Table 2, those in whom statin therapy resulted in CRP levels of less than 2 mg per liter in general had better clinical outcomes regardless of the level of LDL cholesterol achieved. For example, in the group of patients who had LDL cholesterol levels of more than 70 mg per deciliter after statin therapy, the rates of recurrent events were 4.6 per 100 person-years among those with post-treatment CRP levels of more than 2 mg per liter and 3.2 per 100 person-years among those with CRP levels of less than 2 mg per liter. Among patients in whom statin therapy resulted in LDL cholesterol levels of less than 70 mg per deciliter, the respective rates of events were 3.1 and 2.4 per 100 person-years. These differences are presented graphically in Figure 3 in terms of the cumulative incidence of recurrent myocardial infarction or death from coronary causes.

Hazard ratios for recurrent coronary events among patients whose values were above the median for LDL cholesterol and below the median for CRP, those whose values were below the median for LDL cholesterol and above the median for CRP, and those whose values were above the median for both LDL cholesterol and CRP, as compared with those whose values of achieved LDL cholesterol and CRP levels were below the median (the reference group), were 1.3, 1.4, and 1.9, respectively (P for trend across groups <0.001). Almost identical results were observed in analyses that eliminated patients with prior statin use.

Figure 4. Figure 4. Median Levels of CRP at Randomization, 30 Days, 4 Months, and the End of the Study, According to Whether Patients Received 80 mg of Atorvastatin or 40 mg of Pravastatin Daily.

Because study participants were randomly assigned to receive either 80 mg of atorvastatin or 40 mg of pravastatin daily, we had the additional opportunity to assess the relative effect of these two agents on the reduction in CRP levels and to assess whether the main effects observed in the total cohort according to the LDL cholesterol and CRP levels achieved were modified by the choice of statin therapy. With regard to CRP, the median levels were similar in the atorvastatin and pravastatin groups at randomization (12.2 and 11.9 mg per liter, respectively; P=0.60), but they were significantly lower in the atorvastatin group than in the pravastatin group at 30 days (1.6 vs. 2.3 mg per liter, P <0.001), 4 months (1.3 vs. 2.1 g per liter, P <0.001), and the end of the study (1.3 vs. 2.1 mg per liter, P <0.001) (Figure 4).

Despite these differences, there was substantial overlap between the two groups in terms of achieved CRP levels; 57.5 percent of those treated with atorvastatin had CRP levels below 2 mg per liter after 30 days, whereas 44.9 percent of patients in the pravastatin group had such levels (P<0.001). The levels of LDL cholesterol were identical in the two groups at randomization and, as expected, were significantly lower in the atorvastatin group than in the pravastatin group at day 30, four months, and the end of the study. At 30 days, 72.3 percent of those assigned to receive atorvastatin had met the LDL cholesterol goal of a level of less than 70 mg per deciliter, as compared with 21.7 percent of those assigned to pravastatin (P<0.001). The magnitude of the correlation between achieved LDL cholesterol and achieved CRP levels was small for both agents (r=0.04, P=0.07 for pravastatin, and r=0.15, P=0.001 for atorvastatin).

Despite the greater ability of atorvastatin than of pravastatin to reduce LDL cholesterol levels to below 70 mg per deciliter and CRP levels to below 2 mg per liter, there was little evidence that either agent led to better clinical outcomes once the target levels of both LDL cholesterol and CRP were achieved. Specifically, although atorvastatin was superior to pravastatin overall in the PROVE IT–TIMI 22 trial,7 there was no observed residual effect of randomization on clinical outcomes once the achieved levels of LDL cholesterol and CRP were accounted for (fully adjusted hazard ratio for atorvastatin as compared with pravastatin = 1.00; 95 percent confidence interval, 0.75 to 1.34; P=0.90). Similarly, for those in whom atorvastatin therapy resulted in LDL cholesterol levels of less than 70 mg per deciliter, the rates of recurrent events were 3.1 per 100 person-years for those with post-treatment CRP levels of more than 2 mg per liter and 2.3 per 100 person-years for those with CRP levels of less than 2 mg per liter, whereas the corresponding event rates for patients in whom pravastatin resulted in LDL cholesterol levels of less than 70 mg per deciliter were 3.4 and 2.5 per 100 person-years (P=0.70 for the difference between agents). Thus, achieving target levels of both LDL cholesterol and CRP was of substantially greater importance for subsequent event-free survival than was the specific type of statin therapy received.

We performed additional post hoc analyses to evaluate those in whom statin therapy resulted not only in a target LDL cholesterol level below 70 mg per deciliter but also in a CRP level below 1 mg per liter. Although only 15.9 percent of the study population reached these very aggressive target goals, this subgroup had the lowest age-adjusted rate of recurrent events (1.9 per 100 person-years) (Table 2); 81.8 percent of patients in this subgroup had been assigned to receive atorvastatin.

As indicated above, all analyses were adjusted for random assignment to gatifloxacin or placebo. This agent had no significant effect on CRP levels in this population.