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Rosuvastatin for Primary Prevention in Older Persons With Elevated C-Reactive Protein and Low to Average Low-Density Lipoprotein Cholesterol Levels: Exploratory Analysis of a Randomized Trial

Robert J. Glynn, ScD; Wolfgang Koenig, MD; Børge G. Nordestgaard, MD; James Shepherd, MD; and Paul M Ridker, MD
[+] Article and Author Information

From Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; University of Ulm, Ulm, Germany; Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev, Denmark; and the University of Glasgow, Glasgow, United Kingdom.


Grant Support: By AstraZeneca. Dr. Glynn received additional support from the National Institute on Aging (R01 AG18833).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-2155.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Glynn (e-mail, rglynn@rics.bwh.harvard.edu).

Requests for Single Reprints: Robert J. Glynn, ScD, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, Boston, MA 02215; e-mail, rglynn@rics.bwh.harvard.edu.

Current Author Addresses: Drs. Glynn and Ridker: Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, Boston, MA 02215.

Dr. Koenig: Abteilung Innere Medizin II-Kardiologie, Medizinische Universitaetsklinik, Robert-Koch-Strasse 8, D 89081, Ulm, Germany.

Dr. Nordestgaard: Herlev University Hospital, Department of Clinical Biochemistry, Herlev Ringvej 75, DK-2730 Herlev, Denmark.

Dr. Shepherd: North Glasgow University Hospitals, Division of Cardiovascular and Medical Sciences, University of Glasgow, 3rd Floor, MacEwen Building, Glasgow Royal Infirmary, Glasgow G4 OSF, United Kingdom.

Author Contributions: Conception and design: R.J. Glynn, P.M Ridker.

Analysis and interpretation of the data: R.J. Glynn, W. Koenig, P.M Ridker, B.G. Nordestgaard, J. Shepherd.

Drafting of the article: R.J. Glynn.

Critical revision of the article for important intellectual content: R.J. Glynn, W. Koenig, P.M Ridker, B.G. Nordestgaard, J. Shepherd.

Final approval of the article: R.J. Glynn, W. Koenig, P.M Ridker, B.G. Nordestgaard, J. Shepherd.

Provision of study materials or patients: W. Koenig, P.M Ridker, B.G. Nordestgaard.

Statistical expertise: R.J. Glynn.

Obtaining of funding: R.J. Glynn, P.M Ridker.

Administrative, technical, or logistic support: R.J. Glynn, P.M Ridker.

Collection and assembly of data: W. Koenig, P.M Ridker, B.G. Nordestgaard.


Ann Intern Med. 2010;152(8):488-496. doi:10.7326/0003-4819-152-8-201004200-00005
Text Size: A A A

Background: Randomized data on statins for primary prevention in older persons are limited, and the relative hazard of cardiovascular disease associated with an elevated cholesterol level weakens with advancing age.

Objective: To assess the efficacy and safety of rosuvastatin in persons 70 years or older.

Design: Secondary analysis of JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), a randomized, double-blind, placebo-controlled trial.

Setting: 1315 sites in 26 countries randomly assigned participants in JUPITER.

Participants: Among the 17 802 participants randomly assigned with low-density lipoprotein (LDL) cholesterol levels less than 3.37 mmol/L (<130 mg/dL) and high-sensitivity C-reactive protein levels of 2.0 mg/L or more without cardiovascular disease, 5695 were 70 years or older.

Intervention: Participants were randomly assigned in a 1:1 ratio to receive 20 mg of rosuvastatin daily or placebo.

Measurements: The primary end point was the occurrence of a first cardiovascular event (myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes).

Results: The 32% of trial participants 70 years or older accrued 49% (n = 194) of the 393 confirmed primary end points. The rates of the primary end point in this age group were 1.22 and 1.99 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio, 0.61 [95% CI, 0.46 to 0.82]; P < 0.001). Corresponding rates of all-cause mortality in this age group were 1.63 and 2.04 (hazard ratio, 0.80 [CI, 0.62 to 1.04]; P = 0.090). Although no significant heterogeneity was found in treatment effects by age, absolute reductions in event rates associated with rosuvastatin were greater in older persons. The relative rate of any serious adverse event among older persons in the rosuvastatin versus placebo group was 1.05 (CI, 0.93 to 1.17).

Limitation: Effect estimates from this exploratory analysis with age cut-point chosen after trial completion should be viewed in the context of the overall trial results.

Conclusion: In apparently healthy older persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin reduces the incidence of major cardiovascular events.

Primary Funding Source: AstraZeneca.

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

HRT = hormone replacement therapy; hs-CRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol; TG = triglyceride.

* Includes 12 persons for whom age is unknown.

† Randomization was not stratified by age.

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Grahic Jump Location
Figure 2.
Cumulative incidence of the primary and other composite end points, by time, treatment, and age group.

MI = myocardial infarction; VTE = venous thromboembolism. Top. Cumulative incidence of the primary end point (MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes). Middle. Cumulative incidence of the composite end point, including MI, stroke, or any death. Bottom. Cumulative incidence of the composite end point, including the primary end point (MI, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes), VTE, or any death.

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Grahic Jump Location
Figure 3.
Forest plot of the effect of rosuvastatin on the primary end point within subgroups of trial participants 70 years or older.

HRs with 95% CIs are plotted. Incidence rates are per 100 person-years. To convert cholestrol and triglyceride values to mmol/L, multiply by 0.0259 and 0.0113, respectively. BMI = body mass index; HDL-C = high-density lipoprotein cholesterol; HR = hazard ratio; hs-CRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein cholesterol.

Grahic Jump Location

Tables

References

Letters

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Comments

Submit a Comment
Rovastatin for Primary prevention
Posted on April 26, 2010
Marcus M Reidenberg
Weill Cornell Medical College
Conflict of Interest: None Declared

The JUPITER study was limited to people with high C-reactive protein and showed some benefit for all enrolled. Three earlier studies of primary prevention (AFCAP/TEXCAP, PROSPER, AND MEGA) found that the benefit was limited to subjects with low or intermediate HDL. Can the authors further stratify their data by HDL and test if there is differential benefit in groups of people with different baseline HDL values?

Conflict of Interest:

None declared

Letter Regarding Rosuvastatin for Primary Prevention in Older Persons With Elevated C-Reactive Protein and Low to Average Low-Density Liporotein Cholesterol Levels: Exploratory Analysis of A Randomized Trial
Posted on April 26, 2010
Gen-Min Lin
Hualien-Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor: We read with interest the work by Glynn et al which reported that among persons aged 70 years or older in JUPITOR, rosuvastatin was associated with a significant reduction in the rate of a first major cardiovascular event and the safety was also guaranteed (1). Apparently, rosuvastatin was effective in preventing the occurrence of cardiovascular events for most persons with elevated C-reactive protein (hs-CRP) and normal low-density liporotein cholesterol levels (LDL-C). Some characteristics of the cohorts in JUPITOR, not demonstrated before, revealed an inverse association between the body weight index (BMI)/ metabolic syndrome and cardiovascular events regardless of the age. This obesity paradox phenomenon could be reasoned in part for nondiabetic obese persons with normal LDL-C level who were observed without higher rates of cardiovascular hazards in some clinical researches (2). Furthermore, higher hs-CRP levels in obese population (>5 mg/L) may confer greater atheroprotection which were found in animal study (3). Although the author emphasized the absolute treatment benefits of rosuvastatin in the elderly, some subgroups in this population should be weighted the benefits against the hazards in advance. First, we noticed that persons with BMI <25.0 kg/m2 obtained the lowest hazard ratio (HR) of 0.84 within the three stratified BMI subgroups. As the report described, the adverse events rate related to rosuvastatin use in the elderly was higher than that in younger ones. To our best knowledge, low BMI level in addition to the age was the conventional risk factor for statin induced adverse events. Besides, the glomerular filtration rate and serum creatinine level may be overestimated to be good in the elderly and low BMI at baseline. Therefore, the adverse effect of rosuvastatin in this subgroup should be highlighted. Second, those with metabolic syndrome on rosuvastatin treatment had a low HR of 0.79. Since metabolic syndrome was considered to be the most vulnerable predictor to incident diabetes, (4) the subgroup in the elderly population with rosuvastatin induced diabetes should be further identified. In fact, there were more than half of the elderly were women who were at higher risk to have diabetes (HR: 1.5) than men in JUPITOR (5). Accordingly, the hazards of incident diabetes outweighed the benefits of reduction in cardiovascular events for the elderly women with metabolic syndrome on rosuvastatin treatment. Finally, we concluded that both the elderly with low BMI and women with metabolic syndrome needed to pay more attentions on the benefits and adverse effects that rosuvastatin brought about.

References

1. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152: 488-496

2. Barter P, McPherson YR, Song K, Kesaniemi YA, Mahley R, Waeber G, Bersot T, Mooser V, Waterworth D, Grundy SM. Serum Insulin and Inflammatory Markers in Overweight Individuals with and without Dyslipidemia. J Clin Endocrinol Metab 2007; 92:2041-2045.

3. Kovacs A, Tornvall P, Nilsson R, Tegner J, Hamsten A, Bjorkegren. Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia. Proc Natl Acad Sci U S A 2007;104:13768-13773

4. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation. 2005;112:3066-3372

5. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-1077.

Conflict of Interest:

None declared

The hole in JUPITER
Posted on May 17, 2010
David G Sutin
New York University School of Medicine
Conflict of Interest: None Declared

The secondary analysis of the JUPITER study (1) in persons 70 years and older, is very informative, and adds greatly to our knowledge. As pointed out in the accompanying editorial (2), there is a lack of information about the use of statins for primary prevention in patients over age 80 years. The Jupiter study not only includes many of these patients, but even includes 121 patients 85 years or older (3), a group, never yet included in any study of primary cardiovascular prevention with statins. This study led the FDA to approve a new indication for Rosuvastatin for use in Men over 49 years and women over 59 years with elevated high-sensitivity C-reactive protein level and an additional cardiovascular risk factor. The only other randomized study of primary prevention to include patients over age 80, the PROSPER study (4), did not show statistical benefit for Pravastatin in primary prevention in patients aged 70-82 years. The very old have different cardiovascular risk profiles, more co morbidities, more polypharmacy and sensitivity to medication side effects, than the younger old, and therefore deserve to have their data analyzed separately. As a geriatrician, before modifying the way I treat the oldest old, I feel very strongly that a further analysis of the JUPITER data restricted to those over aged 80, is clearly feasible and warranted.

References

1. Glynn RJ, Koenig W, Nordestgaard BG, Shepard J, Ridker PM. Rosuvastatin for Primary Prevention in Older Persons with Elevated C- Reactive Protein and Low to Average Low-Density Lipoprotein Cholesterol Levels: Exploratory Analysis of a Randomized Trial. Ann Intern Med. 2010; 152:488-496

2 . Zieman SJ, Ouyang P. Statins for Primary Prevention in Older Adults: Who is High Risk, Who is Old, and What Denotes Primary Prevention? Ann Intern Med. 2010; 152:528-529

3. Clinical Briefing Document Endocrine and Metabolic Drugs Advisory Committee Meeting December 15, 2009. at http://www.fda.gov/downloads/Advisorycommittees/Committeesmeetingmaterials/Drugs/EndocrinologyandMetabolicdrugsadvisoryCommittee/ucm193831.pdf Accessed on 16 may 2010

4. Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. The Lancet. 2002; 360:1623-30

Conflict of Interest:

None declared

Reverse Epidemiology in JUPITER
Posted on June 3, 2010
Gen-Min Lin
Department of Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor: The phenomenon of reverse epidemiology or obesity paradox has been well recognized in some distinct populations including those with congestive heart failure, end-stage renal disease on dialysis, and the elderly who had lower risk of cardiovascular disease and mortality with obesity (1). Recently, serial post hoc analysis of the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial enrolling a large number of healthy persons with normal lipid profiles and a level of high-sensitive C-reactive protein (hs-CRP) > 2 mg/L also demonstrated the phenomenon of obesity paradox in the placebo arm (2,3). Apparently, rosuvastatin reduced the incidence rates of primary cardiovascular end points in most subgroups in JUPITER reflecting the anti-inflammatory effect of statin on the inhibition of subsequent cardiovascular hazards. However, the impact of obesity and the inflammation status on the final outcome has not been emphasized before. To the best of our knowledge, the possible explanations for reverse epidemiology including malnutrition-inflammation complex syndrome, endotoxin-lipoprotein hypothesis, survival bias and reverse causation except time discrepancies among competitive factors were unlikely present in the healthy cohorts enrolled in JUPITER (4). Accordingly, obese persons with higher levels of hs-CRP and normal lipid profiles, not only for the elderly, experiencing low cardiovascular hazards may have different pathway other than those mentioned above leading to obesity paradox. It has been generally believed that hs-CRP to be an independent or additional risk factor other than low density lipoprotein to cardiovascular disease. In fact, higher levels of hs-CRP should not be seen equally to the severity of the vascular atherosclerosis in healthy obese ones and some evidence supported this concept in animal studies.5 In addition, the composition and distribution of fat tissues may confer different inflammatory insults in obese individuals. For example, the composition of white adipose tissue accounted for energy storage and of release of hormones and cytokines that modulate whole-body metabolism and insulin resistance. On the contrary, brown adipose tissue promoted insulin sensitivity and energy expenditure in the form of thermogenesis mediated by the expression of the tissue-specific uncoupling protein 1. Koster et al further pointed out that metabolically healthy obese older persons (approximately one third of their population) had a more favorable fat distribution, characterized by lower visceral fat and greater thigh subcutaneous fat and a more favorable inflammatory profiles compared to their obese counterparts with metabolic syndrome.6 Therefore, a subsequent investigations to explore the associations of reverse epidemiology among the severity of obesity, levels of hs-CRP and cardiovascular outcomes were suggested.

References

1. Kalantar-Zadeh K, Block G, Howich T, Fonarow GC. Reverse epidemiology of conventional card0iovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 2004; 43: 1439-1444.

2. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C- reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152: 488-496

3. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-1077.

4. Hasper D, Hummel M, Kleber FX, Reindl I, Volk HD. Systemic inflammation in patients with heart failure. Eur Heart J 1998; 19: 761-765.

5. Kovacs A, Tornvall P, Nilsson R, Tegnor J, Hamsten A, Bjorkegren. Human C-reactive protein slows atherosclerosis development in a mouse model with human-like hypercholesterolemia. Proc Natl Acad Sci U S A 2007;104:13768-13773

6. Koster A, Stenholm S, Alley DE , Kim LJ, Simonsick EM, Kanaya AM, Visser M, Houston DK, Nicklas BJ, Tylavsky FA, Satterfield S, Goodpaster BH, Ferrucci L, Harris TB; for the Health ABC Study.. Body fat distribution and inflammation among obese older adults with and without metabolic syndrome. Obesity 2010; DOI:10.1038/oby.2010.86

Conflict of Interest:

None declared

Levels of HDL-Cholesterol, hsCRP, and Metabolic Syndrome in JUPITER
Posted on July 26, 2010
Gen-Min Lin
Hualien Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor: Dr. Ridker and colleagues replied the concern regarding the effects of rosuvastatin for those with different baseline HDL-cholesterol values in JUPITER in the Lancet (1) that was raised by Dr. Reidenberg in Annals of Internal Medicine.(2) Ridker et al pointed out that HDL-cholesterol concentration was strongly predictive of vascular events among those allocated to placebo, but not predictive of residual vascular risk among those treated with potent rosuvastatin therapy who attain very low concentrations of LDL-cholesterol in JUPITER. However we emphasize at least two subgroups without following their rule. As we know, Corsetti et al have found that the epidemiological mappings for a healthy population according to CRP and HDL-cholesterol levels in the PREVEND study revealed two high cardiovascular risk subgroups: a low HDL-cholesterol/ high CRP subgroup and a high HDL-cholesterol/ high CRP subgroup.(3) Obviously, the result contradicted to that of JUPITER. Since the cardiovascular risk functuned of HDL-cholesterol concentration climbs sharply with CRP level elevations in the mappings, those with the lower CRP levels in quartile 4 (3.90 mg/L) may correspond to less cardiovascular rates compared to those with higher CRP levels in other three quartiles 1- 3 in JUPITER. Therefore, the effect of HDL-cholesterol concentrations on cardiovascular rates should be further investigated in different stratified CRP levels. In addition, people with metabolic syndrome were observed up to 81.7% in quartile 1 and the number accounted for half of those with metabolic syndrome in JUPITER. Previously, we have mentioned the reverse epidemiology of JUPITER in this journal,(4) and hence the cardiovascular incidence rates in patients with metabolic syndrome was estimated 1.29/ 100 person-year compared to that without metabolic syndrome was 1.40/ 100- year.(5) If the cardiovascular incidence rate is 1.61/ 100 person-year in quartile 1,(1) we could roughly calculate the cardiovascular incidence rate in those with metabolic syndrome in quartiles 2-4 to be 0.97. Besides, the relative risk for cardiovascular events between groups of rosuvastatin and placebo was estimated to 70% totally,(3)but the relative risk was up to 57% in quartile 1.(1) Accordingly, the relative risk between rosuvastatin and placebo for those with metabolic syndrome in quartiles 2-4 was only 83%. In summary, we conclude that HDL-cholesterol concentration may play a vital role in the metabolic syndrome population in JUPTER and those with most cardiovascular risks occurring in the lowest HDL-cholesterol level quartile 1 obtain the most benefits from rosuvastatin therapy.

References

1. Paul M Ridker, Jacques Genest, S Matthijs Boekholdt, Peter Libby, Antonio M Gotto, Borge G Nordestgaard, Samia Mora, Jean G MacFadyen, Robert J Glynn, John J P Kastelein, for the JUPITER Trial Study Group. HDL cholesterol and residual risk of fi rst cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet, early online publication, 22 July 2010

2. Reidenberg MM. "Rovastatin for Primary prevention" response to Rosuvastatin for primary prevention in older persons with elevated C- reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med published online April 26, 2010

3. Corsetti JP, Gansevoort RT, Sparks CE, Dullaart RP. Inflammation reduces HDL protection against primary cardiac risk. Eur J Clin Invest. 2010; 40: 483-489

4. Lin GM, Chu KM, Han CL. "Reverse Epidemiology in JUPITER" response to Rosuvastatin for primary prevention in older persons with elevated C- reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med published online June 7, 2010

5. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-1077.

Conflict of Interest:

None declared

Rosuvastatin-JUPITER Controversy
Posted on August 2, 2010
Gen-Min Lin
Hualien-Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor: Recently, de Lorgeril et al reported three major flaws regarding the JUPITER trial.(1) First, the clinical data demonstrated a discrepancy between reduction of nonfatal stroke and myocardial infarction (MI) but no effect on mortality from stroke and MI. Second, cardiovascular mortality was relatively low compared with total morality and third, there was a very low case fatality rate of MI. As we know, fatal stroke and MI were observed directly on patient's admission. Certainly, those with nonfatal stroke, MI, and unstable angina accounted for the majority of remaining cardiovascular mortality in JUPITER. The authors criticized that almost half of cardiovascular deaths should be fatal MI,(2) and the rates of confirmed fatal MI was higher in rosuvastatin group (25.7% ) than placebo group (14.0%) in JUPITER. In our opnion, there had some evidence to assure these results. First, the JUPITER trial was designed as prospective observational study and the incidence rates of cardiovascular events were only ascertained when patients were referred to the hospital. Unlike the large populations with MI enrolled in the World Health Organization's MONICA study,(2) the small number of patients suffering MI in JUPITER reflected a major bias as long as some sudden cardiac deaths (SCD) occurred at home and were probably not categorized into confirmed cardiovascular deaths. Accordingly, if we interpreted the JUPITER data on the basis of the findings in MONICA (50% fatal MI), there may be 6 patients died of SCD incorrectly missing in rosuvastatin group and 28 patients in placebo group. This bias was very possibly happened in JUPITER in which near to one third of the population enrolled was elderly over 70 years old.(3) To eliminate the bias, the incidence rate of MI, stroke, and any death should be a better indicator of cardiovascular events than the confirmed cardiovascular deaths that documented in hospital. Actually, the incidence rate of MI, stroke, and any death was still significantly lower in rosuvastatin group than that in placebo (2.7% vs. 4.0%).(3) Many debates were raised regarding JUPITER because the specific cohorts were selected (normal lipid profiles and inflammation). Although there have problems for the benefits of rosuvastatin in some subgroups in JUPITER such as woman with metabolic syndrome, the very elderly and those with low BMI levels,(4,5) we finally believe that the results of the JUPITER trial remain novel and reliable.

References

1. de Lorgeril M, Salen P, Abramson J; et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy: a critical reappraisal. Arch Intern Med. 2010; 170 (12):1032-1036.

2. Tunstall-Pedoe H, Kuulasmaa K, Mahonen M; et al. Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet. 1999; 353 (9164):1547-1557.

3. Glynn RJ, Koenig W, Nordestgaard BG; et al. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152 (8): 488-496

4. Lin GM, Chu KM, Han CL. Letter regarding Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med published online April 27, 2010

5. Sutin DG. "The hole in JUPITER" response to Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med published online May 17, 2010

Conflict of Interest:

None declared

The Elderly and Women With Metabolic Syndrome in JUPITER
Posted on August 12, 2010
Gen-Min Lin
Hualien-Armed Forces General Hospital
Conflict of Interest: None Declared

To the Editor: The pre-specified analyses of JUPTER in the Lancet revealed that patients on rosuvastatin treatment who achieved higher levels of LDL-cholesterol > 1.8mmol/L and hsCRP > 2 mg/L would not obtain any benefits compared to the placebo.(1) Interestingly, rosuvastatin was also found to be less effective in those with hsCRP > 4 mg/L than those with hsCRP <4 mg/L at baseline in JUPITER (relative cardiovascular risk reduction: 30% vs. 59%).(2) Ridker et al declared that use of rosuvastatin was associated with a 50% reduction in LDL-cholesterol and a 37% reduction in hsCRP. Obviously, patients with hsCRP > 4 mg/L at baseline accounted for the majority of those with a therapeutic target hsCRP > 2 mg/L on rosuvastatin treatment. As we know, those with metabolic syndrome, old age, obesity and active smoking have higher levels of hsCRP than general populations. Since the cohorts in JUPITER were selected by a hsCRP level > 2mg/L, the characteristics of these participants were older and overweighed than those in other statin- primary prevention trials. Therefore, which population was associated with extremely high level of hsCRP (> 4mg/L) should be emphasized. In Glynn et al report, we noticed that over 40% patients in JUPITER had a high level hsCRP > 5mg/L regardless of age which equal to those with metabolic syndrome.(3) In addition, the relative risk reduction rate in the subgroup of metabolic syndrome was about 30% in Mora et al report(4) which was also consistent to that of the subgroup with hsCRP > 4 mg/L at baseline.

Ridker et al have pointed that the number of components in healthy women with metabolic syndrome were proportional to the levels of hsCRP. Their epidemiologic study indicated most patients with metabolic syndrome in JUPITER should involve 3 metabolic components at least.(5) Accordingly, we concluded that patients with metabolic syndrome accounted for the majority of those with hsCRP > 4mg/L in JUPITER. Therefore we echo the finding by Ridker et al 1and further put highlight on those with metabolic syndrome in the elderly and women who may be the major populations with the achieved levels of LDL -cholesterol and hsCRP obtained the least benefits from rosuvastatin (relative risk: 80%).(3,4) Ridker et al should let us know in detail the characteristics of these rosuvastatin less or non-responders accounting for one fifth to sixth cohorts in JUPITER and the drug related hazards of incident diabetes and adverse effects in this specific population.

Reference

1. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BrG, Spsherd J, Wilerson JT, Glynn RJ. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation: a prospective study of JUPITER trial. Lancet 2009; 373:1175-1182

2. FDA Website: http://www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs?EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM193831.pdf.

3. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C- reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med 2010;152: 488-496

4. Ridker PM, Buring JE, Cook NR, Rifai N. C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: An 8-Year Follow-Up of 14 719 Initially Healthy American Women. Circulation 2003; 107: 391-397

5. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-1077.

Conflict of Interest: None declared

Acknowledgement and Corrections
Posted on August 15, 2010
Gen-MIn Lin
Hualien-Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor: The therapeutic goal of drugs for patients should always weigh the benefits and hazards. Therefore, to identify who does not need to be treated is as equally important as who is eligible for treatment. In Annals of Internal Medicine, we and some experts have commented on some subgroups in JUPITER that should be cautious with the use of rosuvastatin such as metabolic syndrome patients (especially for women, the elderly and those with HDL levels within quartiles 2-4), the very elderly population (>85 year- old), and the elderly with lower body mass index (<25kg/m2). Of course, those with achieved higher levels of LDL-cholesterol > 1.8mmol/L and hsCRP > 2 mg/L on rosuvastatin should also be identified from JUPITER cohorts to avoid unwanted adverse effects. Here, we make some corrections regarding our letters: 1. Letter published online April 27, 2010: JUPTER substituted for JUPITOR 2. Letter published online July 26, 2010: the sentence "Besides, the relative risk for cardiovascular events, but the relative risk was up to 57% in quartile 1." In fact, it was the risk reduction rate (57%) and hence the relative risk should be corrected to 43%. Consequently, the relative risk between rosuvastatin and placebo for those with metabolic syndrome in quartiles 2-4 should be 97% that has to substitue 83% in the next sentence.

Conflict of Interest:

None declared

A U-Shape Relationship between Stratified hsCRP Levels and Cardiovascular Events in JUPITER
Posted on August 18, 2010
Gen-Min Lin
Hualien-Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor:

Ridker et al announced the relationship of hsCRP levels and cardiovascular events in American Journal of Cardiology that increasing baseline hsCRP levels within JUPITER were nonetheless associated with increasing vascular risk in analyses treating hsCRP as a continuous variable, as an ordinal variable and as a threshold variable.1 Although they present a promising result of positive linear relationship between levels of hsCRP and cardiovascular events especially for men in the tertile and threshold analyses, we map a U-shape curve according to stratified hsCRP levels with a 2mg/L interval (2-4 mg/L, 4-6mg/L, 6-8mg/L, 8-10mg/L and > 10mg/L) obtaining from their threshold analysis in JUPITER (Table). Meanwhile, the effect of rosuvastatin is not like the results Ridker et al found that the relative risk reduction was similar in magnitude across the tertile and threshold levels of entry hsCRP but is reversely ineffective in patients with levels of hsCRP within 6-8 mg/L for both men and women. To interpret these findings in JUPITER, we consider the decline arm of the U-curve functioned of hsCRP levels from 2 mg/L to 8 mg/L that may correlate well to the JUPITER cohorts from those with lower body weight index to higher body weight index/ metabolic syndrome which have been known as reverse epidemiology.2 On the climbing arm of the U curve in high hsCRP levels (>8mg/L), the higher incidence of events may be associated with the populations of the elderly or those with multiple risk factors such as smoking and low body weight index.

The stratified hsCRP model unveils the hidden facts in JUPITER cohorts and reflects a truth that the incidence of cardiovascular events is not only affected by a hsCRP level but also some confounders. Second, whether all patients fulfilled the criteria in JUPITER need rosuvastatin treatment should be further investigated.

References

  1. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein Level to cardiovascular outcomes with rosuvastatin in the Justifications for use of statins in prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER). Am J Cardiol 2010; 106: 204-209
  2. Lin GM, Chu KM, Han CL. Reverse Epidemiology in JUPITER response to Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med published online June 7, 2010

Table. Incidence of cardiovascular primary end point in the JUPITER trial according to stratified hsCRP concentrations.

hsCRP

Patients

Incidence Rate per 100 Person-Year

RR

(mg/L)

(n)

Rosuvastatin

Placebo

Men

2-4

5408

0.59

1.49

0.39

4-6

2327

1.24

1.40

0.89

6-8

1128

1.48

1.13

1.31

8-10

575

0.44

1.94

0.23

> 10

1563

1.07

2.06

0.52

Women

2-4

2797

0.47

1.10

0.42

4-6

1538

0.49

0.77

0.64

6-8

878

0.70

0.42

1.67

8-10

459

0.14

1.44

0.10

> 10

1129

0.93

1.51

0.62

RR = relative risk

Conflict of Interest:

None declared

Rosuvastatin for Those with Intermediate 10-Year Cardiovascular Risk in JUPITER
Posted on August 30, 2010
Gen-Min Lin
Hualien-Armed Forces General Hospital, Hualien, Taiwan
Conflict of Interest: None Declared

To the Editor: We are pleased to see Ridker et al who reported that rosuvastatin 20mg significantly reduces major cardiovascular events among men and women with elevated hsCRP and intermediate risk (5% to 20% 10-year risk) based on Framingham risk score and Reynolds risk score in JUPITER which has been published in Circulation: Cardiovascular Quality and Outcomes.1 This is the first time the authors analyzed their data in conjugation with clinical practice and further implied the fact that rosuvastatin may not be used for those with 10-year cardiovascular risk <5% due to lack of statistic evidence. Certainly, supposed there are very low events rate in the population with low 10-year cardiovascular risk, the prophylactic use of rosuvastatin will not only be cost-ineffective but probably be harmful to persons. Another interesting finding in this report is that rosuvastatin seems to play a risk modifier of primary prevention in JUPITER cohorts and especially for men. In other words, the effectiveness of rosuvastatin equals to one major risk factor deletion in Framingham or Reynolds risk scores leading to the risk ladder downward. For example, the events rate on rosuvastatin arm for those with Framingham 10-year risk of 11% to 20% equals to that on placebo arm with 10-year risk of 5%-10% (0.95 vs 0.92 / 100 person years respectively). Here, we take Framingham risk score for men to calculate and exemplify. Assuming that there are the men aged 50-59 year-old ( 6-8 points), with HDL-cholesterol levels 40-49 mg/dl ( 1 point, the mean value of men in JUPITER) and with systolic blood pressure in normal range (120-129 mmHg) have current smoking status ( 3 points), the total points will be 10-12 that the 10-year risk probability is 6%-10%. However, if they quit smoking, the total points will be 7-9 that the 10- year risk probability is 3%-5%. Obviously, the benefit of rosuvastatin use is similar to the work of quit smoking, lower of blood pressure, elevation of HDL and "return to youth" in Framingham risk score for men. Further, the effect of lower of levels of hsCRP of rosuvastatin may be another direct risk reduction in Reynolds risk score. Finally we congratulate a good start for Ridker et al to elucidate the populations who really benefit from rosuvastatin in JUPITER. In the future, the issues of drug less or non-responders in JUPTER and the association between inflammation and obesity deserve to be emphasized and further discussed.

Reference 1. Ridker PM, Macfadyen JG, Nordestgaard BG, Koenig W, Kastelein JJ, Genest J, Glynn RJ. Rosuvastatin for Primary Prevention Among Individuals With Elevated High-Sensitivity C-Reactive Protein and 5% to 10% and 10% to 20% 10-Year Risk: Implications of the Justification for Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial for "Intermediate Risk" . Circ Cardiovasc Qual Outcomes. 2010 Aug 24. [Epub ahead of print]

Conflict of Interest:

None declared

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Summary for Patients

Rosuvastatin to Prevent Heart Problems and Stroke in Persons 70 Years or Older

The summary below is from the full report titled “Rosuvastatin for Primary Prevention in Older Persons With Elevated C-Reactive Protein and Low to Average Low-Density Lipoprotein Cholesterol Levels: Exploratory Analysis of a Randomized Trial.” It is in the 20 April 2010 issue of Annals of Internal Medicine (volume 152, pages 488-496). The authors are R.J. Glynn, W. Koenig, B.G. Nordestgaard, J. Shepherd, and P.M Ridker.

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