CRP as a Predictor of Benefit from Atorvastatin
CRP as a Predictor of Benefit from Atorvastatin
We report in this trial of hypertensive patients at modest risk of future CV events that baseline CRP independently predicted subsequent CV events but neither baseline levels of CRP nor the achieved levels of CRP on-treatment with atorvastatin 10 mg/day predicted the efficacy of the statin in preventing future CV events. The results of this cohort analysis are similar but more robust than those that we reported from an earlier nested case-control study derived from the same population.
Several studies have shown that baseline CRP is an independent risk predictor of CV events, and this has been confirmed in a recent meta-analysis such that predictive benefits are, at best, modest. Although there remains uncertainty about the relative benefit of CRP for risk prediction, the strength of the association, particularly when potential confounders are incorporated into the models, is weak. We also confirm in this study that there was no interaction between baseline values of CRP and the relative effect of the statin on CV events. These findings are consistent with those reported from the Heart Protection Study, the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial, and the JUPITER (Justification for the Use of statins in Prevention: Intervention Trial Evaluating Rosuvastatin) trial.
Arguably the most controversial and debatable issue concerns the extent to which on-treatment levels of CRP predict the benefits of CV outcome associated with statin therapy. This has been proposed based on analyses of observations of on-treatment levels of CRP from a number of trials, many of which recruited high-risk individuals and, particularly, JUPITER, which recruited low-risk individuals with high CRP.
It has been suggested that data from our earlier nested case-control study in the ASCOT-LLA showed that those who achieved lower levels of on-treatment CRP had a 25% greater relative risk reduction in CV events and that our results were actually compatible with those of other studies. There are flaws in this argument. First, when controlling for confounding variables including CRP and LDL-C at baseline, the absolute difference in risk was 12% (not 25%). Further, those who did not achieve median CRP reduction had an increased risk of 14% in the ASCOT case-control study, with figures of 5% and 12% increased risk in the analyses using complete case data and imputed data, respectively, in the present study. These estimates appear appreciably different from the 47%, 33%, and 26% increased risk reported in the JUPITER trial, A to Z (Aggrastat to Zocor Trial), and PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trial for similar comparisons. Regardless of treatment group assignment in the ASCOT, a 1-mmol/l decrease in LDL-C was shown to be associated with a significant 17% reduced risk of CV and CHD events. A reduction in CRP, however, did not have any association with CV outcome in the ASCOT-LLA population, once reduction of LDL-C was taken into account. Unless the argument is being made that statins are in fact primarily anti-inflammatory drugs (rather than cholesterol-reducing drugs) selective or even additional reporting of the risk reduction association with CRP lowering appears of minimal benefit in delineating the impact of statins on CV risk. Figure 4 clearly shows that once achieved LDL-C is considered, further stratification by achieved CRP has little bearing on the relative risk of CV events. Because about half the patients recruited into the ASCOT-LLA could be categorized as having the metabolic syndrome, thus sharing some characteristics with the JUPITER trial population, we conducted a post hoc subgroup analysis of these patients. Compared with those in the placebo group, among those with the metabolic syndrome, those who were assigned to receive atorvastatin had a higher on-treatment LDL-C and tended to have higher risk of CVD regardless of their on-treatment CRP levels. However, those with lower on-treatment LDL-C and lower on-treatment CRP had a nonsignificant 35% reduced risk of CVD, but there was no evidence of interaction between the metabolic syndrome and on-treatment CRP and LDL-C levels on CVD. Such analyses should be interpreted with caution, however, owing to the limited number of events in individual subgroups.
A further commentary on our earlier findings from the case-control study was made on the grounds of inadequate power. The current study reports on 456 CV events in total, and for the on-treatment CRP analysis in 97 events (with imputed data). This compares with 103 CV events in the JUPITER trial for the on-treatment analysis. Moreover, the JUPITER primary CV endpoint definition included hospitalization for angina, which in the ASCOT CV definition was not considered a hard endpoint and therefore not included. We therefore believe that the power of both studies is comparable. We, however, subsequently conducted a further analysis incorporating 11 cases of the development of unstable angina as a CV endpoint. This made no difference to our original conclusion that those achieving lower levels of LDL-C had a lower risk of CV events regardless of the achieved level of CRP.
Our results showing that on-treatment CRP has virtually no predictive value are in accord with the TNT (Treating New Targets) study, and CARDS (Collaborative Atorvastatin Diabetes Study) (unpublished data) but contrast with other trials performed on patients with acute coronary syndrome, and patients with angiographically documented coronary disease. Investigators have previously claimed that lower levels of CRP after statin therapy predict greater subsequent relative risk reductions in CV events. Unfortunately, none of these studies except REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) reported the relationship of change in CRP (from baseline to follow-up) with events.
Strengths and limitations of the present study require consideration. The relative merits of primary endpoints and power of studies reporting on treatment CRP and CV events were discussed earlier. The present study reports objectively imputed data, although these results are entirely consistent with results from nonimputed data. In terms of relative generalizability, the PROVE-IT and A to Z trials recruited high-risk patients with previous acute coronary events. REVERSAL trials recruited patients with at least 20% stenosis on coronary angiography and with a mean baseline LDL of 3.9 mmol/l and geometric mean CRP of 2.9 mg/l. The JUPITER trial recruited relatively healthy patients with low LDL-C (<3.4 mmol/l) but high CRP (≥2 mg/l), whereas the ASCOT cohort in these analyses included patients without any history of CV and with a median LDL-C of 3.6 mmol/l and a median CRP of 2.4 mg/l at baseline. It is possible that CRP may have a different predictive ability in different patient types. However, we believe that, to date, ASCOT data most usefully reflects patients commonly seen in primary care.
Discussion
We report in this trial of hypertensive patients at modest risk of future CV events that baseline CRP independently predicted subsequent CV events but neither baseline levels of CRP nor the achieved levels of CRP on-treatment with atorvastatin 10 mg/day predicted the efficacy of the statin in preventing future CV events. The results of this cohort analysis are similar but more robust than those that we reported from an earlier nested case-control study derived from the same population.
Several studies have shown that baseline CRP is an independent risk predictor of CV events, and this has been confirmed in a recent meta-analysis such that predictive benefits are, at best, modest. Although there remains uncertainty about the relative benefit of CRP for risk prediction, the strength of the association, particularly when potential confounders are incorporated into the models, is weak. We also confirm in this study that there was no interaction between baseline values of CRP and the relative effect of the statin on CV events. These findings are consistent with those reported from the Heart Protection Study, the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial, and the JUPITER (Justification for the Use of statins in Prevention: Intervention Trial Evaluating Rosuvastatin) trial.
Arguably the most controversial and debatable issue concerns the extent to which on-treatment levels of CRP predict the benefits of CV outcome associated with statin therapy. This has been proposed based on analyses of observations of on-treatment levels of CRP from a number of trials, many of which recruited high-risk individuals and, particularly, JUPITER, which recruited low-risk individuals with high CRP.
It has been suggested that data from our earlier nested case-control study in the ASCOT-LLA showed that those who achieved lower levels of on-treatment CRP had a 25% greater relative risk reduction in CV events and that our results were actually compatible with those of other studies. There are flaws in this argument. First, when controlling for confounding variables including CRP and LDL-C at baseline, the absolute difference in risk was 12% (not 25%). Further, those who did not achieve median CRP reduction had an increased risk of 14% in the ASCOT case-control study, with figures of 5% and 12% increased risk in the analyses using complete case data and imputed data, respectively, in the present study. These estimates appear appreciably different from the 47%, 33%, and 26% increased risk reported in the JUPITER trial, A to Z (Aggrastat to Zocor Trial), and PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trial for similar comparisons. Regardless of treatment group assignment in the ASCOT, a 1-mmol/l decrease in LDL-C was shown to be associated with a significant 17% reduced risk of CV and CHD events. A reduction in CRP, however, did not have any association with CV outcome in the ASCOT-LLA population, once reduction of LDL-C was taken into account. Unless the argument is being made that statins are in fact primarily anti-inflammatory drugs (rather than cholesterol-reducing drugs) selective or even additional reporting of the risk reduction association with CRP lowering appears of minimal benefit in delineating the impact of statins on CV risk. Figure 4 clearly shows that once achieved LDL-C is considered, further stratification by achieved CRP has little bearing on the relative risk of CV events. Because about half the patients recruited into the ASCOT-LLA could be categorized as having the metabolic syndrome, thus sharing some characteristics with the JUPITER trial population, we conducted a post hoc subgroup analysis of these patients. Compared with those in the placebo group, among those with the metabolic syndrome, those who were assigned to receive atorvastatin had a higher on-treatment LDL-C and tended to have higher risk of CVD regardless of their on-treatment CRP levels. However, those with lower on-treatment LDL-C and lower on-treatment CRP had a nonsignificant 35% reduced risk of CVD, but there was no evidence of interaction between the metabolic syndrome and on-treatment CRP and LDL-C levels on CVD. Such analyses should be interpreted with caution, however, owing to the limited number of events in individual subgroups.
A further commentary on our earlier findings from the case-control study was made on the grounds of inadequate power. The current study reports on 456 CV events in total, and for the on-treatment CRP analysis in 97 events (with imputed data). This compares with 103 CV events in the JUPITER trial for the on-treatment analysis. Moreover, the JUPITER primary CV endpoint definition included hospitalization for angina, which in the ASCOT CV definition was not considered a hard endpoint and therefore not included. We therefore believe that the power of both studies is comparable. We, however, subsequently conducted a further analysis incorporating 11 cases of the development of unstable angina as a CV endpoint. This made no difference to our original conclusion that those achieving lower levels of LDL-C had a lower risk of CV events regardless of the achieved level of CRP.
Our results showing that on-treatment CRP has virtually no predictive value are in accord with the TNT (Treating New Targets) study, and CARDS (Collaborative Atorvastatin Diabetes Study) (unpublished data) but contrast with other trials performed on patients with acute coronary syndrome, and patients with angiographically documented coronary disease. Investigators have previously claimed that lower levels of CRP after statin therapy predict greater subsequent relative risk reductions in CV events. Unfortunately, none of these studies except REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) reported the relationship of change in CRP (from baseline to follow-up) with events.
Study Limitations and Strengths
Strengths and limitations of the present study require consideration. The relative merits of primary endpoints and power of studies reporting on treatment CRP and CV events were discussed earlier. The present study reports objectively imputed data, although these results are entirely consistent with results from nonimputed data. In terms of relative generalizability, the PROVE-IT and A to Z trials recruited high-risk patients with previous acute coronary events. REVERSAL trials recruited patients with at least 20% stenosis on coronary angiography and with a mean baseline LDL of 3.9 mmol/l and geometric mean CRP of 2.9 mg/l. The JUPITER trial recruited relatively healthy patients with low LDL-C (<3.4 mmol/l) but high CRP (≥2 mg/l), whereas the ASCOT cohort in these analyses included patients without any history of CV and with a median LDL-C of 3.6 mmol/l and a median CRP of 2.4 mg/l at baseline. It is possible that CRP may have a different predictive ability in different patient types. However, we believe that, to date, ASCOT data most usefully reflects patients commonly seen in primary care.
