- Email: [email protected]
Rosuvastatin, C-reactive protein, LDL cholesterol, and the JUPITER trial
Correspondence
western populations would require statins (which might be excessive without more long-term data). A perhaps more subtle point that readers should consider is that statins are not only anti-inflammatory and cholesterol-lowering, but also partly antithrombotic themselves4 and able to reduce venous thromboembolism.5 If the benefits of rosuvastatin in the JUPITER study are corroborated by another similar study in which aspirin is adequately used, then we should consider broadening statin therapy. I declare that I have no conflicts of interest.
Jeffrey M Bloom
We declare that we have no conflicts of interest.
[email protected]
*J Segura, L M Ruilope
1334 Marsh Street, San Luis Obispo, CA 93401, USA
[email protected]
1
Hypertension Unit, Nephrology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
2
3
4
5
Ridker PM, Danielson E, Fonseca F, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175–83. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002; 136: 161–72. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–79. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279: 1643–50. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360: 1851–61.
Paul Ridker and colleagues1 conclude that, for people who choose to start pharmacological prophylaxis, reductions in both LDL cholesterol and high-sensitivity C-reactive protein are indicators of the success of treatment with statin therapy. In the initial description of the JUPITER study,2 table 1 contains baseline estimated glomerular filtration rates (eGFR) of 73·3 mL/ min/1·73 m² for the rosuvastatin group and 73·6 mL/min/1·73 m² for the placebo group. 1 year later, as shown in table 4, median eGFRs were 66·8 and 66·6 mL/min/1·73 m², 26
respectively.2 According to these data, a relevant proportion of patients included in JUPITER could potentially have established chronic kidney disease (defined as eGFR <60 mL/min/1·73 m²). Chronic kidney disease is characterised by an increased cardiovascular risk and by a positive response to statins.3,4 In our opinion, the frequency of chronic kidney disease should be established in this population, as should whether the positive response to rosuvastatin was affected by the presence of chronic kidney disease.
1
2
3
4
Ridker PM, Danielson E, Fonseca FAH, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175–82. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–207. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004; 110: 1557–63. Navaneethan SD, Pansini F, Perkovic V, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2009; 2: CD007784.
Authors’ reply We agree with Jaime García de Tena that smoking cessation, blood pressure control, and lifestyle modification remain important for primary prevention. However, half of all vascular events occur among those with average or low concentrations of cholesterol. JUPITER showed that targeting statin therapy to those with elevated highsensitivity C-reactive protein (hsCRP) and low LDL cholesterol reduces heart attack and stroke by 50% and total mortality by 20%. Similar benefits were seen among those with elevated hsCRP and no other major risk factors. In our paper and webappendix, we show that the effects of hsCRP are independent of LDL cholesterol and
the ratios of apolipoprotein B to apolipoprotein A and of LDL cholesterol to HDL cholesterol. We also present in paragraph 4 of the Results data on outcomes stratified by baseline LDL cholesterol and hsCRP. Thus, the information sought by both W E Feeman and Nicolas Danchin are already provided. JUPITER did not enrol patients with low LDL cholesterol and low hsCRP because we previously saw within the AFCAPS/TexCAPS trial1 that such individuals have a very low absolute risk and did not benefit from statin therapy. Whereas Robert Rosenstein and David Parra focus on p values within specific subgroups, our prespecified analyses assessed trends across levels of achieved LDL cholesterol and achieved hsCRP where effects are highly significant (p<0·0001). The independent data and safety monitoring board was highly experienced and followed rigorous principles in their prespecification that early termination would require proof beyond a reasonable doubt. The board elected to continue the trial for an additional 6 months after the conservative stopping boundary was crossed. Data that accrued thereafter independently confirmed both the magnitude and statistical significance of the main effects. We thus believe the board protected the interests of society and the trial participants and provided a valid estimate of treatment effect.2 Cut-points for both LDL cholesterol and hsCRP were not arbitrary but prespecified on the basis of previous work.3 In continuous rather than categorical analyses, we obtain largely similar results, as suggested by our use of percentage reductions in addition to absolute reductions. Allan Sniderman is correct in that achieved levels depend in part on baseline characteristics, and our analyses therefore adjusted for a wide range of baseline covariates including LDL cholesterol, hsCRP, and HDL cholesterol. Only 1% of the placebo-allocated group achieved LDL cholesterol concentrations of less than www.thelancet.com Vol 374 July 4, 2009
western populations would require statins (which might be excessive without more long-term data). A perhaps more subtle point that readers should consider is that statins are not only anti-inflammatory and cholesterol-lowering, but also partly antithrombotic themselves4 and able to reduce venous thromboembolism.5 If the benefits of rosuvastatin in the JUPITER study are corroborated by another similar study in which aspirin is adequately used, then we should consider broadening statin therapy. I declare that I have no conflicts of interest.
Jeffrey M Bloom
We declare that we have no conflicts of interest.
[email protected]
*J Segura, L M Ruilope
1334 Marsh Street, San Luis Obispo, CA 93401, USA
[email protected]
1
Hypertension Unit, Nephrology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
2
3
4
5
Ridker PM, Danielson E, Fonseca F, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175–83. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002; 136: 161–72. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–79. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279: 1643–50. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360: 1851–61.
Paul Ridker and colleagues1 conclude that, for people who choose to start pharmacological prophylaxis, reductions in both LDL cholesterol and high-sensitivity C-reactive protein are indicators of the success of treatment with statin therapy. In the initial description of the JUPITER study,2 table 1 contains baseline estimated glomerular filtration rates (eGFR) of 73·3 mL/ min/1·73 m² for the rosuvastatin group and 73·6 mL/min/1·73 m² for the placebo group. 1 year later, as shown in table 4, median eGFRs were 66·8 and 66·6 mL/min/1·73 m², 26
respectively.2 According to these data, a relevant proportion of patients included in JUPITER could potentially have established chronic kidney disease (defined as eGFR <60 mL/min/1·73 m²). Chronic kidney disease is characterised by an increased cardiovascular risk and by a positive response to statins.3,4 In our opinion, the frequency of chronic kidney disease should be established in this population, as should whether the positive response to rosuvastatin was affected by the presence of chronic kidney disease.
1
2
3
4
Ridker PM, Danielson E, Fonseca FAH, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175–82. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195–207. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004; 110: 1557–63. Navaneethan SD, Pansini F, Perkovic V, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2009; 2: CD007784.
Authors’ reply We agree with Jaime García de Tena that smoking cessation, blood pressure control, and lifestyle modification remain important for primary prevention. However, half of all vascular events occur among those with average or low concentrations of cholesterol. JUPITER showed that targeting statin therapy to those with elevated highsensitivity C-reactive protein (hsCRP) and low LDL cholesterol reduces heart attack and stroke by 50% and total mortality by 20%. Similar benefits were seen among those with elevated hsCRP and no other major risk factors. In our paper and webappendix, we show that the effects of hsCRP are independent of LDL cholesterol and
the ratios of apolipoprotein B to apolipoprotein A and of LDL cholesterol to HDL cholesterol. We also present in paragraph 4 of the Results data on outcomes stratified by baseline LDL cholesterol and hsCRP. Thus, the information sought by both W E Feeman and Nicolas Danchin are already provided. JUPITER did not enrol patients with low LDL cholesterol and low hsCRP because we previously saw within the AFCAPS/TexCAPS trial1 that such individuals have a very low absolute risk and did not benefit from statin therapy. Whereas Robert Rosenstein and David Parra focus on p values within specific subgroups, our prespecified analyses assessed trends across levels of achieved LDL cholesterol and achieved hsCRP where effects are highly significant (p<0·0001). The independent data and safety monitoring board was highly experienced and followed rigorous principles in their prespecification that early termination would require proof beyond a reasonable doubt. The board elected to continue the trial for an additional 6 months after the conservative stopping boundary was crossed. Data that accrued thereafter independently confirmed both the magnitude and statistical significance of the main effects. We thus believe the board protected the interests of society and the trial participants and provided a valid estimate of treatment effect.2 Cut-points for both LDL cholesterol and hsCRP were not arbitrary but prespecified on the basis of previous work.3 In continuous rather than categorical analyses, we obtain largely similar results, as suggested by our use of percentage reductions in addition to absolute reductions. Allan Sniderman is correct in that achieved levels depend in part on baseline characteristics, and our analyses therefore adjusted for a wide range of baseline covariates including LDL cholesterol, hsCRP, and HDL cholesterol. Only 1% of the placebo-allocated group achieved LDL cholesterol concentrations of less than www.thelancet.com Vol 374 July 4, 2009