More Data From PROVE IT-TIMI 22

A Special Report

By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.

A recent journal of the American College of Cardiology contains a Focus Issue section, consisting of 3 articles about PROVE IT-TIMI 22 and a state of the art paper relating to the lipid independent or pleiotropic affects of statins in the management of acute coronary syndromes (ACS). The previously reported main PROVE IT-TIMI 22 trial randomized over 4000 individuals with ACS to a moderate or intensive LDL lowering strategy. A less potent drug, pravastatin 40mg, was compared to atorvastatin 80mg. Average follow-up was 24 months (18-36 months). Patients were randomized to a statin within 10 days of hospitalization for ACS. The primary end point was reduced by 16%. The first article is a post hoc analysis of early and late events in the PROVE IT-TIMI 22 trial, focusing on the 30-day window after admission, as well as long-term follow up from 6 months to the end of the study. The analysis mirrors the data from the primary report, and somewhat arbitrarily breaks down the overall results into 2 time periods. Thus, the composite end point in the atorva patients vs prava had a risk reduction of 24%, P = 0.0002, with an average duration of follow-up of 2 years. When early effects alone were analyzed, there was a 15% risk reduction within 15 days (NS). At 4 months, the primary end point was achieved by 8.2% of patients in the intensive (atorva) arm vs 10.2% on prava, risk reduction of 19%, P = 0.03. Using a different multiple end point, risk reduction was 28% at 30 days with atorva (P = 0.046), CRP levels were lower at 30 days and 4 months with atorva. Late effects of statin treatment (6 months to end of study) resulted in an 18% hazard reduction with atorva, P = 0.037, and a separate conditional hazard analysis from 1 year to the end of the follow-up demonstrated a 28% risk reduction with atorva, P = 0.02. The composite triple end point was also positive for atorva, with a 28% risk reduction, P = 0.003 by study end. The authors suggest that the early benefits in the high dose statin cohort "…occur before the greater reductions in LDL-C with intensive statin therapy are likely to have had any significant effect." They stress that the greater CRP reduction in the intensive therapy group supports "…greater early anti-inflammatory pleiotropic affects with intensive statin therapy." They conclude that all ACS patients should receive high-dose intensive statin therapy in hospital, and that the statin "should be continued long-term."

Safety of Intensive Statin Therapy

The second article by Wiviott and colleagues reports on possible adverse outcomes with intensive lipid lowering, compared to the moderate pravastatin group. This analysis only involved the intensive treatment arm, who had greater lowering of LDL cholesterol and presumably a greater degree of potential risk. The primary efficacy analysis used a composite end point with multi-variable analysis for differences in baseline characteristics, such as age, gender, and diabetes. Crude rates of safety were reported, including evaluation of hemorrhagic stroke and liver enzymes. The results in the 2100 patients randomized to atorvastatin 80mg were quite reassuring, with infrequent muscular side effects and no rhabdomyolysis. Furthermore, there was no relationship between achieved LDL and muscle symptoms. There were no ophthalmologic events. Of interest, there was no correlation between the degree of LDL reduction and increased liver enzymes. Ten percent of the entire atorvastatin cohort achieved LDL levels < 40 mg/dL, and fully 25% were < 50 mg/dL. There was no increase in adverse events in these subjects. The lowest achieved LDL levels tended to have lower baseline LDL concentrations, more commonly found in older males, diabetics, and those who had not utilized statin therapy. Wiviott et al point out that PROVE-IT-TIMI-22 "is the largest long-term specific study of the safety of high-dose atorvas- tatin published to date." They note that adverse events were few, and suggest that the data are most reassuring. Regarding efficacy, they suggest that "further LDL lowering beyond the new guideline optimal goal of less than 70 mg/dL may translate into an additional clinical benefit." Wiviott et al note that TNT, HPS, and A to Z are all comparable with respect to statin efficacy, as related to the potency of statins. Wiviott et al point out that this analysis is post-hoc, and they emphasize that PROVE-IT used single doses of 2 statins; thus, other agents or combinations might not have fared so well.

Inflammation and Statins

The third article in this series evaluated the relationship between uncontrolled risk factors and C-reactive protein (CRP) levels in patients receiving standard or intensive statin therapy for ACS. This evaluation consisted of 2885 patients on either atorvastatin or pravastatin who had metabolic markers and CRP measurements available at 4 months; these patients reflect approximately 70 % of the entire study. Four-month CRP levels were correlated with multiple variables, including BMI, systolic blood pressure, glucose, LDL, and triglycerides. Furthermore, smoking, diabetes, and "uncontrolled metabolic risk factors" were factored into the analysis. Multi-variant analyses were utilized using log CRP and multiple risk factors. The relationships between risk factors were relatively weak, although independently associated with higher CRP, and included age, female sex, BMI, smoking, LDL > 70 mg/dL, glucose > 110 mg, and HDL < 50 mg/dL. Uncontrolled risk factors demonstrated a direct relationship between CRP levels for both statins. Nevertheless, randomization to the intensive group was associated with a lower CRP in spite of uncontrolled risk factors, and this was true across all strata. Wiviott et al conclude that "a more intensive statin regimen consistently achieved lower CRP levels in 4 months…independent of lipid levels in the presence of CV risk factors." The highest CRP levels were noted in individuals with the greatest number of metabolic and/or lifestyle risk factors, with an approximate 0.3-0.5 mg/dL greater CRP increment for each risk factor present. Lower numbers of risk factors were associated with lower CRP. CRP levels were lower in the intensive group when compared to the standard group (pravastatin), no matter how many risk factors were present. Wiviott et al suggest that there may have been greater pleiotropic effects related to statin dose (intensive arm) via interaction with intercellular mechanisms, including Rho/Rho kinase pathways, lipid rafts, etc. They point out that although there was a weak relationship between achieved CRP and LDL, as cited in the initial publication of PROVE-IT1, there is at least some interaction between the 2 variables. The final conclusions are that high-dose statin therapy "was independently associated with significantly lower CRP levels irrespective of the number of type of risk factors present." They suggest that CRP might be valuable as a global barometer of the effectiveness of lifestyle and other interventions that modify CV risks.

Pleiotrophic Effects of Statins

The last paper in this Focus Issue deals with the potential relevance of multiple lipids independent or pleiotropic effects of statins. This is a thorough review of many studies that suggest the importance of such lipid independent actions, including the effect of these drugs on endothelial cells, thrombosis, markers of coagulation, and the interaction between stains and inflammation. Considerable basic science work is reviewed with excellent diagrams, demonstrating a wide variety of putative mechanisms. It is of interest that there are indeed many potential alterations relating to the effects of statins in ACS, as formulated by Wiviott et al. Thus, in addition to the evidence for CRP lowering with statins in clinical trials, these drugs produce reductions in ICAM-1, e-selection, IL-1, IL-6, and soluble CD40-ligand. The timing of event curve separations is an issue of scrutiny, in that stable CAD patients generally have a much later curve separation and statistical evidence of benefit from LDL cholesterol lowering than in ACS, where available data indicate very rapid favorable alterations, with early statin initiation. Finally, Wiviott et al conclude that "the highest statin doses may be important for early clinical benefits in ACS patients." They suggest that the "lipid independent effects of statins…may contribute to the early reduction in cardiovascular risk observed with intensive statin therapy in ACS."

Commentary

For those readers particularly interested in the issues of statin therapy, acute coronary syndromes, and mechanisms of benefit, it is worth reading these articles, particularly the last one, which is not a study, but a well written comprehensive review of potential pleiotropy in ACS. There is clearly some aspect of data dredging in this focused review of PROVE-IT-TIMI-22. The first 3 papers all reconfirm statin efficacy, as well as safety in the aggregate, but nothing particularly new is noted. The authors' observations and conclusions that early intensive statin therapy is particularly beneficial in ACS is of considerable interest. Nevertheless, many papers have indicated that patients who are on statin, or who are put on statin during a hospitalization for ACS, fare well, and a very recent publication even indicates day one statin use is related to favorable outcomes. Although the results of MIRACL, the first randomized controlled trail in ACS, were disappointing to many, they now seem to be more valid; the relatively modest benefits in that study has been amplified by the larger and longer studies such as PROVE IT-TIMI-22. The TNT study in stable CAD patients supports the favorable data in the core PROVE IT paper, as well as in these 3 additional publications, as does the REVERSAL trial. It would appear that in high-risk individuals, particularly those with an ACS or perhaps with a multiplicity of risk factors, very aggressive LDL lowering to achieve a target of 70 mg/dL or less, is no longer a fairy tale, and should be a reality for all practicing physicians caring for these patients.

References

1. Cannon C, et al. Intensive Versus Moderate Lipid Lowering With Statins After Acute Coronary Syndromes. N Engl J Med. 2004;350:1495-1504.

2. Ray K, et al. Early and Late Benefits of High-Dose Atorvastatin in Patients With Acute Coronary Syndromes: Results From the PROVE IT-TIMI 22 Trial. JACC 2005;46:1405-1411.

3. Wiviott S, et al. Can Low Density Lipoprotein Be Too Low? The Safety and Efficacy of Achieving Very Low Low-Density Lipoprotein With Intensive Statin Therapy: A PROVE IT-TIMI 22 Substudy. JACC. 2005;46:1417-1424.

4. Ray K, et al. Relationship Between Uncontrolled Risk Factors and C-Reactive Protein Levels in Patients Receiving Standard or Intensive Statin Therapy for Acute Coronary Syndromes in the PROVE IT-TIMI 22 Trial. JACC. 2005;46:1417.

5. Ray K, Cannon C. The Potential Relevance of the Multiple Lipid-Independent (Pleiotropic) Effects of Statins in the Management of Acute Coronary Syndromes. JACC. 2005;46:1425.