使用降血脂 statin 預防心血管疾病 JUPITER

2026-01-21 08:29AM

研究名稱縮寫 JUPITER(全文pdf)

使用20mg rosuvastatin 與安慰劑做比較 (台灣常開的劑量是 10mg)

受試者 1萬7802人. 

收納條件 LDL < 130 且 high-sensitivity C-reactive protein ≥2 mg/L. 

實驗終點有好幾種.心肌梗塞、中風、血管重建或死亡

JUPITER試驗的5年NNT為20（95% CI，14至34）。

所有亞組的5年NNT值均低於50。

1. 性別: 男性5年需治療人數（NNT）為17，女性為31；

2. 種族: 白人為21，非白人為19；

3. 肥胖程度: 體重指數≤25 kg/m²者為18，體重指數>25 kg/m²者為21 ；

4. 遺傳: 有冠心病家族史者為9，無冠心病家族史者為26；

5. 有代謝症候群者為19，無代謝症候群者為22；

9. 弗雷明漢風險評分大於10%者為14，弗雷明漢風險評分小於10%者為37。

pdf檔案: Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)—Can C-Reactive Protein Be Used to Target Statin Therapy in Primary Prevention?

Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin 

Number Needed to Treat With Rosuvastatin to Prevent First Cardiovascular Events and Death Among Men and Women With Low Low-Density Lipoprotein Cholesterol and Elevated High-Sensitivity C-Reactive Protein: Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)

方法和結果－

利用「他汀類藥物預防應用合理性：一項評估瑞舒伐他汀的干預試驗」（JUPITER）的數據，計算了一系列終點、時間範圍和亞組的絕對風險降低值和相應的需治療人數（NNT）值。 JUPITER是一項隨機對照試驗，評估了瑞舒伐他汀20 mg與安慰劑的療效，受試者為17802名低密度脂蛋白膽固醇<130 mg/dL且高敏C反應蛋白≥2 mg/L的健康男性和女性。此外，也進行了敏感性分析，以探討其他他汀類藥物方案可能對類似一級預防族群產生的影響。

對於心肌梗塞、中風、血管重建或死亡此終點，JUPITER試驗的5年NNT為20（95% CI，14至34）。所有亞組的5年NNT值均低於50。

例如，男性5年需治療人數（NNT）為17，女性為31；

白人為21，非白人為19；

體重指數≤25 kg/m²者為18，體重指數>25 kg/m²者為21 ；

有冠心病家族史者為9，無冠心病家族史者為26；

有代謝症候群者為19，無代謝症候群者為22；

弗雷明漢風險評分大於10%者為14，弗雷明漢風險評分小於10%者為37。

對於包含靜脈血栓栓塞在內的淨血管獲益終點，5年NNT為18（95% CI，13至29）。

對於限制性「硬終點」（心肌梗塞、中風或死亡），5年NNT為29（95% CI，19至56）。

在評估替代藥物理論效用的敏感性分析中，分別針對能達到JUPITER研究中觀察到的相對獲益75%和50%的他汀類藥物方案，估計其5年需治療人數（NNT）值分別為38和57。

所有這些計算結果均優於先前報告的用於高血脂男性一級預防的他汀類藥物（5年NNT為40至70）、抗高血壓治療（5年NNT為80至160）或阿斯匹靈（5年NNT>300）的5年NNT值。
結論—對於高敏 C 反應蛋白升高和低密度脂蛋白膽固醇降低的患者，他汀類藥物治療的絕對風險降低和相應的 NNT 值與已發表的幾種廣泛接受的心血管疾病一級預防干預措施的 NNT 值相當，甚至更優，其中包括對明顯高脂血症患者使用他汀類藥物治療。

The most important action of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is their ability to lower levels of low-density lipoprotein (LDL) cholesterol. Statins have proved highly effective in reducing the risk of cardiovascular events in both primary and secondary prevention studies. However, the magnitude of risk reduction associated with statins is greater than that predicted on the basis of LDL cholesterol lowering alone. A likely explanation for this effect is the antiinflammatory action of statins. Following the observation that high-sensitivity C-reactive protein (hs-CRP) is a powerful predictor of cardiovascular events, investigators in the Cholesterol and Recurrent Events (CARE) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) trials demonstrated that the magnitude of risk reduction associated with statin therapy was higher among those with elevated hs-CRP levels. In addition, there is accumulating evidence that statins lower plasma levels of hs-CRP in a manner largely independent of LDL cholesterol lowering. In contrast, little benefit has been demonstrated for statin therapy in the absence of both hyperlipidemia and inflammation. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a large multinational, long-term, double-blind, placebo-controlled, randomized clinical trial designed to assess directly whether statin therapy (rosuvastatin 20 mg/day) should be given to apparently healthy individuals with low LDL cholesterol levels but elevated hs-CRP levels—a critical issue for the prevention of cardiovascular disease. Support for the concept behind the JUPITER trial is also now available from several recent trials comparing different intensities of statin therapy on disease progression as well as clinical end points. These studies indicate that the hs-CRP level achieved after initiation of statin therapy may be as important as the LDL cholesterol level achieved. All of these data raise the possibility that hs-CRP could be used to target high-risk patients who may benefit from early statin use. Ongoing work will determine whether hs-CRP reduction, independent of LDL cholesterol reduction, results in a net clinical benefit. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006; 97[suppl]:33A– 41A) 

Numerous avenues of research ranging from basic experimental evidence to population-based observational studies have led to the recognition that cardiovascular disease (CVD) involves a systemic inflammatory process.1 Large epidemiologic studies carried out in diverse populations have repeatedly documented the association between highsensitivity C-reactive protein (hs-CRP), an indicator of inflammation, and CVD outcomes, independent of traditional cardiovascular risk factors.2 However, it remains uncertain whether therapies that lower hs-CRP levels would also result in lower cardiovascular event rates. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely studied lipid-lowering agents and the most effective low-density lipoprotein (LDL) cholesterol–lowering medications. Statins lower LDL cholesterol and total cholesterol levels by approximately 20% to 50% and have a lesser effect on lowering triglycerides (
10% to 40%) and raising high-density lipoprotein (HDL) cholesterol (
5% to 15%) levels. Most studies of the effect of statins on outcomes have shown that for approximately every 1% reduction in LDL cholesterol level, there is an associated 1% reduction in risk of clinical cardiovascular events.3 Data from multiple large-scale randomized clinical trialssupport a similar relative risk reduction with statin therapy for cardiovascular outcomes in both the primary and the secondary prevention of CVD. This has led to the development of current international guidelines that focus on LDL cholesterol lowering as the primary target of therapy, tailoring the level of optimal LDL cholesterol reduction to the individual’s level of cardiovascular risk.3 Several risk prediction models, such as the Framingham risk equations and the European Systematic Coronary Risk Evaluation (SCORE), use traditional risk factors to estimate global CVD risk in asymptomatic individuals.4,5 However, most US women and a large proportion of US men are classified as low risk when the Framingham risk score, as recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, is used to estimate risk in the primary prevention setting. Current US population estimates from the National Health and Nutrition Examination Survey (NHANES) found that 1% of women had high-risk Framingham scores (10-year estimated risk for hard coronary events of 20%) and only 4% of women had intermediate-risk scores (10% to 20%), compared with 5% and 29% in men, respectively.6 Meanwhile, the lifetime risk of developing CVD for both men and women is substantiallyhigher—approximately 1 in 3 for women and 1 in 2 for men

To improve cardiovascular risk stratification and detection, an expert panel assembled by the Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA) provided a scientific statement on hs-CRP summarizing how it may be applied for clinical cardiovascular risk assessment in primary prevention populations.8 This report termed hs-CRP an independent marker of cardiovascular risk and endorsed its use as part of global risk prediction in asymptomatic individuals, particularly those deemed at intermediate risk for CVD by traditional risk factors.8 The panel also established a set of cut points to be used in clinical practice, with hs-CRP levels of 1 mg/L considered low risk and 3 mg/L, high risk. The Cholesterol And Recurrent Events (CARE) trial first demonstrated that statin therapy also lowers plasma levels of hs-CRP.9 This has since been shown to be a class effect, with an approximate statin-mediated reduction of hs-CRP levels of 20% to 30%.9,10 However, the beneficial value of lowering hs-CRP that is independent of lowering LDL cholesterol is not so clear.

The critical question then becomes whether inflammatory markers, such as hs-CRP, can be clinically useful in selecting patients who may benefit from statin therapy despite having normal LDL cholesterol values. This is the hypothesis driving Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a long-term, multinational, randomized, double-blind, placebo-controlled study to assess rosuvastatin 20 mg in the primary prevention of cardiovascular events in 15,000 subjects with low LDL cholesterol levels and elevated levels of hs-CRP.

Role of Inflammation in Cardiovascular Disease 

Multiple large-scale prospective studies performed in a variety of populations have demonstrated that hs-CRP is a strong and independent predictor of CVD events, including myocardial infarction (MI), ischemic stroke, sudden cardiac death, and diabetes mellitus.11–22 In the Physicians’ Health Study, an epidemiologic study of 22,000 healthy middleaged men with no clinical evidence of disease, increasing levels of hs-CRP at study entry were associated with up to a 3-fold increase in risk of incident MI and a 2-fold increase in risk of ischemic stroke.12 When directly compared with other novel risk factors—including homocysteine, lipoprotein(a), interleukin-6, intercellular adhesion molecule–1, and serum amyloid A—and standard lipid measures, hsCRP has proved to be the single strongest predictor of cardiovascular risk in apparently healthy women. This is demonstrated in the Women’s Health Study (Figure 1), with a relative risk ratio of 4.4 for the highest versus lowest quartile of hs-CRP.

Moreover, the addition of hs-CRP to traditional cholesterol screening enhanced cardiovascular risk prediction and proved to be independent of LDL cholesterol, suggesting that elevated hs-CRP levels may be particularly useful for identifying asymptomatic individuals who may be at high risk for future cardiovascular events but who have average cholesterol levels. As shown in Figure 2, the poorest eventfree survival in women was among those with high LDL cholesterol and high hs-CRP levels, and the best event-free survival was among those with low LDL cholesterol and low hs-CRP levels. Notably, individuals with low LDL cholesterol levels but high hs-CRP levels were at higher risk than those with high LDL cholesterol levels but low hs-CRP levels. This important finding of higher risk associated with high hs-CRP/low LDL cholesterol is among the motivating factors behind the JUPITER trial because this population of apparently healthy individuals— usually missed by current screening guidelines—is being prospectively studied for the first time.Levels of hs-CRP add important prognostic information on cardiovascular risk not only at all levels of LDL cholesterol but also at all levels of the Framingham risk score (Figure 3). With increasing levels of global coronary risk (Figure 3, left), there was a graded and consistent relation with increasing levels of hs-CRP in a dose-response manner. This additional prognostic information is most clinically relevant for those asymptomatic individuals who are at intermediate risk for CVD based on their traditional risk factor profile (Framingham risk estimate of 5% to 20% for developing coronary artery disease over a 10-year period). Currently, these individuals are not considered eligible for aggressive risk factor modification with statin therapy because their LDL cholesterol levels are below the current therapeutic target of 3.36 mmol/L (130 mg/dL).3 The JUPITER trial was designed to study just this population. The ability of hs-CRP to add prognostic information on global cardiovascular risk after adjustment for all Framingham risk factors has been confirmed in 9 major prospective studies (Figure 4). The hs-CRP marker has also been found to modify the risk associated with the metabolic syndrome, which encompasses a number of proatherogenic, prothrombotic, and proinflammatory risk factors (abdominal obesity, elevated triglycerides, low HDL cholesterol levels, high blood pressure, and high fasting glucose levels).16 This finding may be because of the active role that adipocytes play in inflammatory vascular processes, particularly in central or abdominal tissue. The metabolic syndrome has been associated with increased cardiovascular risk and thus was identified as a target of therapy in NCEP ATP III.3 Individuals with the metabolic syndrome are more likely to have high hs-CRP levels, and those with 1 or 2criteria for the metabolic syndrome have higher hs-CRP levels than those with none. In a study of 14,000 apparently healthy women, median hs-CRP levels for those with 0, 1, 2, 3, 4, or 5 criteria for the metabolic syndrome were 0.68, 1.09, 3.01, 3.88, and 5.75 mg/L, respectively.16 In individuals who met NCEP ATP III criteria for the metabolic syndrome, those with high levels of hs-CRP (
3 mg/L) had worse event-free survival than those with low hs-CRP levels (3 mg/L). Figure 5 shows cardiovascular event-free survival in analyses stratified by hs-CRP levels of 1, 1 to 3, and 3 mg/L, which are cutoffs chosen to correspond with CDC recommendations for differentiating low-, intermediate-, and high-risk groups.8 As clearly shown, hs-CRP levels added information at all levels of the metabolic syndrome, just as prior data had demonstrated that hs-CRP added important prognostic information at all levels of LDL cholesterol and at all levels of the Framingham risk score.

Although a number of different markers of inflammation can provide useful information for predicting cardiovascular risk, acute-phase reactant hs-CRP is currently the most accurate marker.23 Inflammatory markers, such as soluble intercellular adhesion molecule–1 and interleukin-6, are not readily measured in clinical settings, partly because of their instability and partly because of measurement error. In contrast, several commercial assays with acceptable coefficients of variation are available for the measurement of CRP, and a program to standardize CRP testing is currently being developed by the CDC.8 Emerging evidence also suggests that hs-CRP may not only be a useful marker of inflammation but may also play an active role in the pathogenesis of atherosclerosis (Figure 6). Specifically, CRP appears to be directly involved in augmenting the innate inflammatory response; inducing prothrombotic factors, such as plasminogen activator inhibitor–1, proinflammatory adhesion molecules, and monocyte chemoattractant protein–1; and interfering with endothelial nitric oxide synthase.24 –27 Recent studies have shown that CRP is produced not only in the liver, as previously believed, but also locally in other tissues, including smooth muscle cells from normal coronary arteries and diseased coronary artery bypass grafts.28,29 Moreover, CRP transgenic mice that were made to overexpress the human CRP gene developed significant thrombosis after arterial damage, suggesting that hs-CRP may be more than just a marker for atherosclerosis.

C-Reactive Protein–Lowering Effects of Statins in Acute Coronary Syndromes 

Until recently, it was not known whether the hs-CRP– lowering action of statins provided any clinical benefit beyond their LDL cholesterol–lowering action. In 2 studies published recently—the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) and the Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction 22 (PROVE IT– TIMI 22) studies—the strongest evidence to date is provided for the independent cardiovascular benefits associated with statin-induced hs-CRP lowering.30,31 These 2 trials compared the effects of high-dose atorvastatin with those of low-dose pravastatin, demonstrating that lowering hs-CRP levels through intensive statin therapy reduced progression of coronary plaque and risk of recurrent clinical events in patients with acute coronary syndromes. In PROVE IT–TIMI 22, there was a highly significant relative reduction of CVD events (16%) favoring high-dose statin therapy at a 2.5-year follow-up—although the benefit was seen as early as 30 days from the start of therapy.

A prespecified analysis of PROVE IT–TIMI 22 revealed similar and statistically independent relations between hs-CRP reduction and risk of recurrent coronary events and between LDL cholesterol reduction and risk of such events. When patients were divided into categories on the basis of final hs-CRP and LDL cholesterol levels achieved, those with hs-CRP levels reduced to 2 mg/L had fewer recurrent events, regardless of the LDL cholesterol level achieved by statin therapy. As shown in Figure 7, the patients at highest risk were those in whom both LDL cholesterol and hs-CRP remained elevated despite statin therapy. In patients whose LDL cholesterol was lowered to below study median (1.8 mmol/L [70 mg/dL]) with statin use, those whose hs-CRP levels remained elevated had significantly higher recurrent event rates than those whose CRP levels were reduced to 2 mg/L. Moreover, the correlation between hs-CRP reduction and LDL cholesterol reduction achieved by statin use was small in both trials (correlation coefficient, 0.1 to 0.2). These findings suggest that the beneficial effects of statin therapy for secondary prevention of cardiovascular events may be as much a result of lowering hs-CRP levels as lowering LDL cholesterol levels. REVERSAL demonstrated that lowering hs-CRP levels in patients with coronary disease by intensive statin therapy resulted in reduced atherosclerotic lesion progression; in some patients there was even atheromatous regression, as measured by intravascular ultrasonography (Figure 8). These findings suggest that to maximize the benefit of statin therapy, physicians may need to monitor hs-CRP levels in addition to LDL cholesterol levels for secondary prevention of CVD. JUPITER will clarify whether such monitoring could also be beneficial for primary prevention.

Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) 

Because inflammation is an integral part of the underlying pathophysiology of atherosclerosis and hs-CRP is a useful clinical marker of this inflammatory process, an important unresolved question is whether hs-CRP screening combined with traditional lipid screening would provide an improved strategy for statin use in primary prevention of CVD. The JUPITER trial was designed to answer this question. Several factors governed the design. First, statin therapy has been repeatedly demonstrated to lower the risk of CVD events. Second, several studies have now shown statins to have a greater impact on lowering CVD risk in individuals with higher levels of inflammation.32,33 As already noted, for example, investigators in the CARE trial of secondary prevention found that the benefit of pravastatin was greater among subjects with elevated hs-CRP levels.32 Similarly, in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) of primary prevention with lovastatin, the event reduction among those with low LDL cholesterol but high hs-CRP was virtually identical to that seen in patients with high LDL cholesterol.33 Third, more than half of CVD events occur in individuals with LDL cholesterol levels that current guidelines do not consider eligible for therapy. And finally, because of the hs-CRP–lowering effects of statins, treating individuals with high hs-CRP levels but normal LDL cholesterol levels may extend the benefit of prophylactic statins. The primary objective of the JUPITER trial is to determine whether statin therapy (rosuvastatin 20 mg/ day) will reduce the rate of first major cardiovascular events, defined as the combined primary end point of cardiovascular death, MI, stroke, hospitalization for unstable angina, or arterial revascularization among healthy individuals with low LDL cholesterol levels (3.36 mmol/L [130 mg/dL]) but high hs-CRP levels (
2 mg/ L).34 Figure 9 shows the basic JUPITER trial design. Asymptomatic individuals (men aged 55 years, women aged 65 years) who have no prior history of MI, stroke, or myocardial revascularization and who on initial screening are found to have LDL cholesterol levels 3.36 mmol/L (130 mg/dL) and hs-CRP levels
2.0 mg/L are randomized in a double-blind manner to either rosuvastatin 20 mg/day or placebo. All study participants are then observed over a period of 3 to 4 years for the development of a first cardiovascular event. JUPITER has been designed to answer definitively whether those with average or low LDL cholesterol levels but high hs-CRP levels should be treated aggressively with statin therapy to lower their risk of CVD events. Secondary objectives of JUPITER are to evaluate whether rosuvastatin therapy lowers the incidence of type 2 diabetes mellitus, bone fractures, and venous thromboembolism. Given the large sample size and the inclusion of a large number of women and minorities, the study will also provide an important tool for evaluating the safety of longterm rosuvastatin use in various racial and ethnic groups.

Conclusion 

The JUPITER trial is the first large-scale, multinational, double-blind, placebo-controlled clinical trial to investigate the effects of statins in the primary prevention of cardiovascular events in individuals with low levels of LDL cholesterol who may be at risk because of their elevated hs-CRP levels. Trial results could provide an evidence base for the use of hs-CRP in addition to LDL cholesterol to guide statin therapy in primary prevention. Because of its potential impact on public health, this trial represents an extremely important step in understanding the links among inflammation, statin therapy, and CVD prevention— knowledge that could lead to substantial alterations in our approach to cardiovascular prophylaxis and treatment.

Abstract

Background— As recently demonstrated, random allocation to rosuvastatin results in large relative risk reductions for first cardiovascular events among apparently healthy men and women with low levels of low-density lipoprotein cholesterol but elevated levels of high-sensitivity C-reactive protein. However, whether the absolute risk reduction among such individuals justifies wide application of statin therapy in primary prevention is a controversial issue with broad policy and public health implications.

Methods and Results— Absolute risk reductions and consequent number needed to treat (NNT) values were calculated across a range of end points, timeframes, and subgroups using data from Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a randomized evaluation of rosuvastatin 20 mg versus placebo conducted among 17802 apparently healthy men and women with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥2 mg/L. 

Sensitivity analyses were also performed to address the potential impact that alternative statin regimens might have on a similar primary prevention population. For the end point of myocardial infarction, stroke, revascularization, or death, the 5-year NNT within JUPITER was 20 (95% CI, 14 to 34). All subgroups had 5-year NNT values for this end point below 50; as examples, 5-year NNT values were 17 for men and 31 for women, 21 for whites and 19 for nonwhites, 18 for those with body mass index ≤25 kg/m2 and 21 for those with body mass index greater than 25 kg/m2, 9 and 26 for those with and without a family history of coronary disease, 19 and 22 for those with and without metabolic syndrome, and 14 and 37 for those with estimated Framingham risks greater or less than 10%. For the net vascular benefit end point that additionally included venous thromboembolism, the 5-year NNT was 18 (95% CI, 13 to 29). For the restricted “hard” end point of myocardial infarction, stroke, or death, the 5-year NNT was 29 (95% CI, 19 to 56). In sensitivity analyses addressing the theoretical utility of alternative agents, 5-year NNT values of 38 and 57 were estimated for statin regimens that deliver 75% and 50% of the relative benefit observed in JUPITER, respectively. All of these calculations compare favorably to 5-year NNT values previously reported in primary prevention for the use of statins among hyperlipidemic men (5-year NNT, 40 to 70), for antihypertensive therapy (5-year NNT, 80 to 160), or for aspirin (5-year NNT, >300).

Conclusions— Absolute risk reductions and consequent NNT values associated with statin therapy among those with elevated high-sensitivity C-reactive protein and low low-density lipoprotein cholesterol are comparable if not superior to published NNT values for several widely accepted interventions for primary cardiovascular prevention, including the use of statin therapy among those with overt hyperlipidemia.

Clinical Trial Registration— clinicaltrials.gov. Identifier NCT00239681.