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Statins and primary prevention of cardiovascular events- Editorials
  (see responses following the main Editorial)
Published 14 November 2008, doi:10.1136/bmj.a2576
Cite this as: BMJ 2008;337:a2576
No change in strategy is needed despite the hype surrounding the recent JUPITER study
This week, the New England Journal of Medicine published the randomised controlled trial JUPITER,1 which compared rosuvastatin (20 mg daily) with placebo in 18 000 patients with no apparent vascular disease, low density lipoprotein cholesterol (LDL-C) of less than 3.4 mmol/l (130 mg/dl), and high sensitivity C reactive protein concentrations of 2.0 mg/l or higher. The combined primary end point was myocardial infarction, stroke, arterial revascularisation, hospital admission for unstable angina, or death from cardiovascular causes. The trial was stopped after a median of two years after a highly significant improvement in the primary end point with rosuvastatin (hazard ratio 0.56; 95% confidence interval 0.46 to 0.69; P<0.00001). It is hardly surprising that the JUPITER study is seen by many as opening the door to new avenues to prevention.
What do the results mean? Do we really have to change our ways of targeting our preventive efforts-for example, measure high sensitivity C reactive protein on a regular basis? Although the relative risk reduction is impressive, the absolute risk puts the results into perspective. Of 100 people in the control arm, 1.36 experienced a primary outcome within one year, and this was reduced to 0.77 by the intervention. Although this was significant, its clinical relevance is doubtful. Participants were free of vascular disease, but half of them had a Framingham risk score >10%, and more than a third had the metabolic syndrome. A closer look at subgroup analyses (size of plots, exact numbers are not reported) indicates that most events occurred in high risk groups. Wouldn't old fashioned risk estimation by traditional methods have produced similar results?
The relative risk reduction (44%) was also much higher than in previous trials. Although the authors suggest that measuring C reactive protein allows the selection of a group of patients who benefit more than others, alternative explanations should be considered. Because participants in both the intervention and control groups had low concentrations of LDL-C, controls were presumably not taking non-study statins. This is in contrast to many previous trials, where up to 17% of patients in the control group were taking non-study statins, which diluted the positive effect.2 3 Moreover, a four week placebo run-in phase allowed the JUPITER investigators to select highly compliant patients. This also limits the external validity of the trial.
Although the JUPITER investigators talk about a "strategy" based on measurement of LDL-C and C reactive protein, this is not what they studied. In fact, they present a conventional drug trial on a highly selected group of patients. Testing a strategy in a pragmatic trial would have to involve measuring high sensitivity C reactive protein in addition to detecting conventional risk factors to identify patients like the ones included in JUPITER. In a control arm only the usual risk factors would be used to target treatment at high risk patients. A trial of this kind conducted in relevant settings, such as primary care, is needed before a strategy that includes measuring high sensitivity C reactive protein can be routinely recommended. Only then can we know whether the additional complexity and cost (high sensitivity C reactive protein is measured differently from conventional C reactive protein) would translate into reduced disease outcomes.Furthermore, from a recent analysis of the Framingham study we learn that the additional prognostic value of laboratory measurements is negligible.4 Against the hype of new tests and drugs we should not forget that to work at a population level interventions have to be simple and easily reproducible.
So what can we learn from the JUPITER trial? Firstly, that rosuvastatin is efficacious and safe. This is important because a previous trial with rosuvastatin 10 mg versus placebo was negative, with a non-significant relative risk reduction of only 8%.5 However, because rosuvastatin was not compared directly with simvastatin and other statins, we do not know whether it is really better. Until we know that, established (and cheaper) statins should be preferred. Secondly, statins work independently of LDL-C concentrations, but in low risk populations the effects on absolute risk are small. Thirdly, this study-in which almost half of the subjects were below the target level for LDL-C lowering in ischaemic heart disease-makes the whole concept of lipid lowering to a specific LDL-C target look more obsolete than before. Instead of lowering lipids we should talk about global cardiovascular risk assessment. Statins with their multiple actions are an effective means to improve the prognosis of high risk patients, as are aspirin and antihypertensive drugs. Possible effects should be discussed with patients,6 and if doctor and patient agree that a statin is indicated, a fixed dose should be given.7
All this is hardly new. No change in practice is warranted on the basis of the JUPITER study. Future studies should evaluate alternative strategies of risk assessment and intervention in usual care settings that may include measuring high sensitivity C reactive protein. Current preventive practices should be reconsidered only if an effect can be shown in a pragmatic study.
Cite this as: BMJ 2008;337:a2576
Norbert Donner-Banzhoff, professor1, Andreas Sonnichsen, professor2
1 Department of General Practice, University of Marburg, D-35032 Marburg, Germany, 2 Institute of General Practice, Paracelsus Medical University, A-5020 Salzburg, Austria Provenance and peer review: Commissioned; not externally peer reviewed.
1. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. N Engl J Med 2008;359:2195-207.
2. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
3. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:1998-3007.
4. D'Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care. Circulation 2008;117:743-53.
5. Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JGF, Cornel JH, et al, for the CORONA Group. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61
6. Krones T, Keller H, Sonnichsen A, Sadowski EM, Baum E, Wegscheider K, et al. Absolute cardiovascular disease risk and shared decision making in primary care: a randomized controlled trial. Ann Fam Med 2008;6:218-27.[
7. Donner-Banzhoff N, Sonnichsen A. Strategies for prescribing statins. BMJ 2008;336:288-9.
Rapid Responses published:
High level of hs-CRP should be treated with statin irrespective of lipid profile.
Gauranga Dhar (16 November 2008)
Maybe JUPITER will change something
Mikael Rabaeus (16 November 2008)
Re: Maybe JUPITER will change something
Alexander Jablanczy (18 November 2008)
Early Interruption of Jupiter Trial
Ken Leeper (19 November 2008)
Three more "fatal myocardial infarctions" in rosuvastatin group than placebo in JUPITER
Malvinder S Parmar (20 November 2008)
JUPITER: no cardiovascular deaths prevented
Eddie Vos, Colin P. Rose, MD (27 November 2008)
High level of hs-CRP should be treated with statin irrespective of lipid profile.
16 November 2008
Gauranga Dhar,
Physician and teacher Bangladesh Institute of Family medicine and Research. Dhaka, Bangladesh-01209
Chronic inflammation is the most important factor for atherosclerosis. Among the inflammatory biomarkers, hs-CRP plays crucial role. Bogalusa heart study shows that atherosclerosis starts in early childhood. Cigarette smoking, HTN, hyperglycemia, obesity, hyperlipidemia cause endothelial dysfunction and subsequent increased production of hs- CRP with the help of IL-6. Increased level of hs-CRP is directly proportional to cardiovascular outcomes. Besides metabolic factors written above there are so many other reasons which cause elevated level of hs- CRP. For example bacteria C. pneumoniae, H. pylori, Herpes simplex infection can also stimulate atherosclerosis. Recent study in Denmark showed decreased rate of mortality in adults hospitalized due to pneumonia who were under prior statin therapy. Main cause of death of patients with rheumatoid arthritis is atherosclerotic disease e.g. heart attack. This is due to high rise of inflammatory markers like hs-CRP and TNF alpha as well. Resent study in Russia (Ref:PMID: 18991814 [PubMed - in process]) has shown that HMG-CoA- reductase inhibitors, statins reduce hs-CRP level more rapidly in patients with RA than in patients with IHD which subsequently may reduce cardiovascular outcomes in patients with RA. According to me, statin is an unique drug, use of which will be extended in other indications other than lowering lipid parameters. Reserches now under way to use statins plus antibiotics in acute and chronic infections. I think irrespective of lipid profile, use of statins will give beneficial effects in adults in terms of cardiovascular outcomes. In my practice I will start to screen my suspected adult patients for hs-CRP level and if high, I will go for statin.
Competing interests: None declared
Maybe JUPITER will change something
16 November 2008
Mikael Rabaeus,
Medical Director
Health Management Center, Clinique de Genolier, 1272 Switzerland
Credit should be given to the BMJ and Drs Donner-Banzhoff and Sonnichsen for tempering the unpleasant hype that followed the publication of the JUPITER trial, hailed as a "ground-breaking trial that will change the paradigm of cardiovascular prevention"... In addition to the very pertinent remarks by the authors of the BMJ editorial, I would like to point out that the methodology in itself of the study is far from stain-free :
- it is hard to find any good reason to interrupt the study early, considering the very low absolute benefit
- the mortality figures (the only that cannot be discussed) show an even lower absolute reduction of 0.25 % (NNT = 400). Curiously, a short time before the study was interrupted, the reduction was only around 0.1 % (NNT = 1000), according to the curves shown. To say the least, the study was interrupted at a very convenient moment...
- the competing interests are staggering. In particular, the first author and chair of the steering committee is a co-inventor of the hs-CRP test which has been licensed to Astra-Zeneca.
JUPITER should simply be discarded, being irrelevant and to the least doubtful in its conclusions.
In fact, one might speculate as to whether it actually doesn't add evidence to the fact that statins are probably much less efficient than we want to believe. I would like to remind everybody of the CORONA trial (N. Engl. J. Med. 2007;357:2248-61.)in which rosuvastatin as compared to placebo had no benefit whatsoever on clinical outcomes in HIGH-risk patients (CAD patients with heart failure) Maybe JUPITER will change something in our daily practice : we should consider closely if our patients really are in need of statins. M. Rabaeus MD
Competing interests: None declared
Re: Maybe JUPITER will change something
18 November 2008
Alexander Jablanczy,
private office, Sault Ste Marie
Of course I cannot read your article as evidently your interest is not spreading light but the darkness of Mammon. My wife tells me while we supposedly pay $25 dollars a month for this accursed internet actually somehow it works out to be $800 for three months. So I never pay for anything they must be stealing this somehow.
So I cannot comment on the actual figures of this study, but when the whole kerfuffle about the hormone replacement therapy came out in JAMA a few years ago it was accessible on the internet and since then any study I can get my hands on is pretty much the same.
I use four coloured pens for easy explanation to myself and patients. It refers to that study but is applicable to this and any other.
I draw two lines in blue ten thousand units long assuming the study had 10,000 subjects.
Then I draw inside that line a segment 9900 units long in green. This of course means that whether or not the whole group got this or that treatment placebo or drug 9900 people or subjects didnt die or suffer any ill effects.
Of the remaining 100 unit length I colour at the end black the last fifty. This of course means that whichever they belonged to fifty died anyway in either group.
So we are left with fifty to colour red who died only in one group.
Now the reporters of these studies have the audacity to say that there was say fifty % reduction in death rate because they compare the fifty red plus fifty black with the fifty red. But they fail to mention the glaringly obvious that we started with 10,000 not 100 which is a bit of a difference.
So my humble contention is that a much less than one percent difference is simply inconsequential. You have this massive majority of over 9900 to whom any ministrations of a pharmaceutical simply made no difference wahtsoever. If I gave you ten thousand talents but keep ten or five as retainer fee do you really give a damn? Now it's true if you are one of the five survivors it makes all the difference in the world, but for the others it's immaterial. So half a percent has a different ring to it than fifty percent.
Competing interests: nil except that I am an MD
Early Interruption of Jupiter Trial
19 November 2008
Ken Leeper,
General Practitioner
Billinghay Medical Practice Billinghay Lincoln LN4 4AU UK
I believe the scientific community must unite behind the basic principle that it is unacceptable to interrupt a clinical trial early - unless it is clearly shown that the study arm is more dangerous to patients than the currently accepted standard treatment.
This is especially important for trials like Jupiter where the proposed intervention is to be promoted for long term use.
Clearly drug manufacturers and authors seeking maximum kudos will want trials stopped at a time that shows the intervention in its best light - as others have already commented.
It is perfectly feasible that adverse effects of continuing the intervention may have outweighed benefits before the planned end of the trial.
This trial has been stopped before providing any evidence of long- term benefit. It must be robustly criticized for this. However it could become a useful trigger for an internationally accepted standard that future trials could be expected to adhere to.
I would propose that all trials seeking to demonstrate long-term benefits from new interventions should be expected to run for at least 5 years in most cases.
Participants in trials are treated shabbily, possibly unethically, when trials are stopped early in this manner. They deserve better - and future generations depend on better standards of research.
Let us all now unite to bring to an end such unprofessional behaviour.
Competing interests: None declared
Three more "fatal myocardial infarctions" in rosuvastatin group than placebo in JUPITER
20 November 2008
Malvinder S Parmar,
Associate professor, Northern Ontario School of Medicine
640 Ross Ave. East, Suite E, Timmins, ON. P4N 8P2, Canada
There is no doubt that results of JUPITER [1] are intriguing and interesting. However, one needs to study the information in detail, before changing practice drastically.
The way the data is presented raises some questions and concerns.
1. hs-CRP was used as entry criteria and many different sub-group analyses were presented in the paper BUT an important one, if not the most important, about what happened to patients in this group whose CRP didn't come down. What was the difference in event rates in this group of patient's. This analysis should have been included.
2. In Table 3 [page 2201] of the original paper in NEJM, the authors report results of non-fatal myocardial infarction [22 in active group versus 62 in control group p<0.00001] and in the line below they report "any myocardial infarction" [31 in active group and 68 in control group p0.0002]. Ideally, the categories should have been 'any MI' and "fatal MI' but here some thinking did go into presenting the data, that should favour active agent where possible. They didn't define what they mean by 'any myocardial infarction' and I deduce from the data that,
"Any myocardial infarction" = "fatal myocardial infarction" + "non- fatal myocardial infarction," and, that could be STEMI or NSTEMI.
So, if the above deduction is correct, which likely is, then rosuvastatin group had 9 'fatal MIs' [31-22 =9] whereas the control group had 6 [68-62=6]. So Active group had three more "fatal myocardial infarctions" and this indicates that the results were likely camouflaged knowingly [likely] or unknowingly [let's give a benefit of doubt] and this should be taken into consideration. Although, only 3 more fatal MI's but these are the real 'hard-end" points. If a 0.01% difference in HbA1C could be statistically significant, then this hard end point with a difference of 3 bodies should not only be statistically but clinically significant.
3. Interestingly, there were total 142 primary end points in rosuvastatin group compared to 251 in placebo BUT any death '198' were significantly higher than the primary end points in rosuvastatin group, compared to control group. So, if the patients didn't die from cardiovascular disease, they did die for other reasons. The fact that the numbers don't match here is somewhat interesting and requires further clarification.
1. Ridker PM et al. Rosuvastatin to prevent vascular events in Men and women with elevated C-reactive protein. NEJM 2008; 359:2195-207
Competing interests: None declared
JUPITER: no cardiovascular deaths prevented
27 November 2008
Eddie Vos,
maintains health-heart-org
Sutton (Qc) Canada J0E 2K0,
Colin P. Rose, MD
In support of this excellent Editorial, we add the following: 4 of the 5 combined primary endpoints were non fatal: two were "disease" [myocardial infarction and (probably ischemic) stroke], the 3rd was a treatment option [revascularization, a procedure without evident mortality benefit and being 90% determined by the first hospital visited in an acute coronary syndrome: ref. ], a 4th was hospitalization for unstable angina [a non-significant 41% on -statin reduction] and, finally, "confirmed death from cardiovascular causes", an endpoint that was not reported separately. However, calculating back from NEJM's Table 3, there would have been a TOTAL of 31 vascular fatalities in the rosuvastatin vs. 37 in the placebo groups, a highly non-significant difference.
As in many statin studies, could the 3 non-fatal endpoints in which benefit was found be from statin's nitroglycerin mimicking action [by promoting NO-synthase], in which case using a drug like nitroglycerin directly, and thus reducing angina, would have shown the same non-fatal primary endpoint benefit? Something that should finally be investigated.
Competing interests: None declared
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