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MEDICAL FRONTIERS - 58th Annual Scientific Session of the American College of Cardiology

Orlando, Florida / March 29-31, 2009

Two new sets of data, both delivered as latebreakers at the 2009 annual ACC scientific sessions, greatly expand the populations who can expect to benefit from intensive lipid lowering. The data were drawn from JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), which previously associated intensive lipid lowering with a 44% reduction (P<0.00001) in the composite end point of myocardial infarction (MI), stroke, revascularization, hospitalization for unstable angina or cardiovascular (CV) death. The study was conducted in patients with elevated high-sensitivity C-reactive protein (hsCRP) but without hyperlipidemia. The highly significant protection against venous thromboembolism (VTE), a prespecified secondary end point, is immediately relevant to the practical advantages of this strategy.

“VTE, which can be a serious and even life-threatening event, was found to be about as common as MI and stroke in the study population. Rosuvastatin reduced the incidence of VTE without any evidence of an increased risk of bleeding,” reported Dr. Robert Glynn, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. JUPITER is the first randomized trial to prospectively confirm protection against VTE. There was no heterogeneity in the VTE reduction across major subgroups, such as those defined by age, gender or weight. The reduction in VTE was not secondary to the reduction in CV events.

JUPITER Background

JUPITER has been a landmark for its ability to extend the lipid hypothesis by redefining the point at which lipid lowering extends CV protection. In JUPITER, which randomized 17,802 apparently healthy men over the age of 50 and women over the age of 60 to 20 mg once daily of rosuvastatin or placebo, the two most important entry criteria were plasma levels of LDL-C <3.4 mmol/L and hsCRP <u>></u>2.0 mg/L. The Data Safety Monitoring Committee recommended termination of the study after a median of 1.9 years of a planned five-year follow-up due to the of overwhelming benefit in the active treatment arm.

VTE Risk

In the latest analysis, rosuvastatin was associated with a 43% reduction (HR 0.57; 95% CI, 0.37-0.86; P=0.007) in the risk of VTE relative to placebo (Figure 1). The magnitude of the protection against VTE was large both in those with unprovoked events, meaning VTE in the absence of known causes such as trauma, surgery, or malignancy, and in those with provoked events. The protection against VTE was not correlated with the protection against CV events. There was no association of rosuvastatin or protection from VTE with an increased risk of bleeding, a notable departure from other strategies to prevent VTE. In JUPITER, bleeding events occurred in 2.9% of those randomized to rosuvastatin and 3.1% of those randomized to placebo (P=0.45).

Figure 1.

The reduction in VTE substantially lowers number-needed-to-treat (NNT) calculations for benefit. Reviewing the NNT for the outcomes evaluated in JUPITER, Dr. Glynn reported that the 44% reduction of the primary end point yielded a NNT of 25. By adding VTE to the combined primary end point, the NNT falls to 21. When the 20% relative reduction in total mortality is calculated in a NNT that includes the primary outcome and VTE, the figure falls to 18 (Figure 2). According to Dr. Glynn, “These numbers are very favourable when compared to accepted strategies such as treatment of hypertension o
rin.”

Figure 2.

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Dual Target Therapy

Although JUPITER reinforces the benefit of large LDL-C reductions, including those that bring LDL-C levels below those identified as the target in current guidelines, the ability to select candidates for treatment with hsCRP, a marker of inflammation, is important new information. According to the principal investigator of JUPITER, Dr. Paul Ridker, also affiliated with Brigham and Women’s Hospital, these results “tell us that atherosclerosis is a process mediated by both elevated lipids and inflammation.” Although it is still not known whether hsCRP is a treatable risk factor, a new analysis of JUPITER data demonstrates that reductions in LDL-C and hsCRP independently predict benefit.

“Those who achieved a LDL-C concentration of less than 1.8 mmol/L and a hsCRP of less than 2.0 mg/L did better than those that did not achieve either target or those that achieved the LDL-C target alone,” Dr. Ridker told delegates.

In an analysis published in The Lancet (epub ahead of print March 29, 2009), the hazard ratios for the reduction in the primary end point was stratified for patients who achieved an LDL-C <1.8 mmol/L or <u>></u>1.8 mmol/L according to an end-of-study hsCRP (<2.0 mg/L or <u>></u>2.0 mg/L). Risk reductions in the on-treatment patients were compared to placebo after adjusting for a substantial number of variables, including age, baseline LDL-C, blood pressure, body mass index, smoking status, and family history. This analysis revealed that the benefits in those with both a low LDL-C and a low hsCRP were additive and independent.

Specifically, while there was no treatment benefit relative to placebo in those patients with an on treatment hsCRP <u>></u>2.0 mg/L and LDL-C <u>></u>1.8 mmol/L, the relative event reduction was 58% (HR 0.42; 95% CI, 0.18-0.94; P<0.0001) even with LDL-C >1.8 mmol/L if the hsCRP <2.0 mg/L. If the hsCRP <u>></u>2.0 mg/L but LDL-C <1.8 mmol/L, the relative risk reduction was 47% (HR 0.53; 95% CI, 0.38-0.74; P<0.0001). If both LDL-C <1.8 mmol/L and hsCRP <2.0 mg/L, the risk reduction was 65% (HR 0.35; 95% CI, 0.23-0.54; P<0.0001). Using a cutoff of hsCRP <1.0 mg/L, the risk reductions tended to be tighter. In those with LDL-C <1.8 mmol/L and a hsCRP <1.0 mg/L, the risk reduction in the primary composite end point reached 79% (HR 0.21; 95% CI, 0.09-0.51; P<0.0001), which is unprecedented in a primary prevention lipid-lowering trial. All of these reductions were observed after adjusting for baseline characteristics, reinforcing the evidence that the reductions and the clinical benefits were derived from medication effects.

Lipid Lowering Still of Paramount Importance

These findings appear to be critical in the effort to understand the mechanism of protection provided by statins in CV risk reduction. Although Dr. Ridker noted that greater LDL-C lowering can be associated with greater reductions in markers of inflammation regardless of statin, he repeatedly emphasized that the correlation between reductions in LDL-C and hsCRP in individual patients is small. Dr. Ridker stated that less than 2% of the variance in achieved hsCRP could be explained by the variance in achieved LDL-C in JUPITER. This explains why both values provided the best predictive value of CV protection.

Other benefits are also possible. When asked to speculate on the mechanism of protection against VTE, Dr. Glynn offered that elevated lipid levels have not been strongly associated with increased risk of VTE in previous studies. Although he suggested that there is a stronger association between VTE and inflammatory markers, he remarked, “We think what we are seeing with rosuvastatin may be due to an anticoagulatory action.” In response to a question about class effect, Dr. Glynn acknowledged, “I have no idea,” although he indicated such studies are needed.

At this point, hsCRP remains a marker of risk and not a target of treatment. JUPITER demonstrated that hsCRP can be used to identify patients who will benefit from aggressive lipid lowering even though their LDL-C levels would not warrant therapy by current guidelines. However, JUPITER also provides evidence that in such patients, it is the reduction in LDL-C rather than the on-treatment level of LDL-C which is the best predictor of protection. This is an important shift from current guidelines, which identify specific targets for specific risk groups.

Dr. Ridker addressed delegates, “My own feeling, based on the data, is that it is the percentage reduction of LDL-C and hsCRP from the starting point that will determine the relative risk reduction,” indicating that there may be no absolute lipid level that determines risk or absence of risk of CV events. Elevated levels of hsCRP may explain why some patients with relatively low lipid levels remain at elevated CV risk. An elevated hsCRP may identify patients who require substantial reductions in LDL-C even when their initial values are not remarkable.

Asked to comment on these data, Dr. Jacques Genest, Director, Division of Cardiology, Royal Victoria Hospital, McGill University, Montreal, Quebec, stated that the focus should remain on LDL-C reductions even if when those at risk are identified by other markers such as hsCRP. He noted that one of the most important contributions of JUPITER is that it has reiterated that message.

“When you decrease LDL-C, you reduce the risk of having a CV event,” stated Dr. Genest, who remarked that the very large LDL-C reductions in JUPITER were well tolerated, safe and provided a high degree of relative protection against events. Although the overall results reinforce the premise that “lower is better” without any plateau yet identified, he concurred with Dr. Ridker that relative reductions might be as important as the target reached. Based on JUPITER, a reduction of at least 50% from baseline appears to be both safe and beneficial.

Summary

The protection against VTE in a secondary outcome analysis from JUPITER has expanded the relative benefits of a relatively modest dose of rosuvastatin achieved in a population selected by an elevated hsCRP rather than by hyperlipidemia. When considered on top of the large reduction in the primary composite end point of major CV events, this additional benefit has substantially reduced the NNT that calculates relative benefit. Although the intensive lipid lowering provided by rosuvastatin is likely to be the primary driver of the risk reductions, new analyses strongly correlate hsCRP with an independent predictive value and provide a basis to further explore the mechanisms of this approach to risk management. In addition, LDL-C reductions of at least 50% ma
an a target LDL-C in predicting relative protection.

Figure 3.

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