SEARCHing for JUPITER: starry-eyed optimismis not warranted

The SEARCH trial recruited 12,064 patients, 83%

men, of who 41% had myocardial infarcts, 40%

coronary interventions, 7% stroke, 22% peripheral

vascular disease and 105 with diabetes. Concurrent

therapies consisted of aspirin in 89%, beta-blockers

51%, angiotensin-converting enzyme inhibitors

(ACE-Is) 46% and 28% diuretics. Patients were statin

experienced, and in that 72% had received prior sta-

tins which comprised simvastatin of 60% (3). Baseline

therapy with simvastatin 20 mg gave a total choles-

terol of 4.2 mmol ⁄ l, triglycerides of 1.9 mmol ⁄ l,high-density lipoprotein cholesterol (HDL-C) of

1.00 mmol ⁄ l and low-density lipoprotein cholesterol

(LDL-C) of 2.5 mmol ⁄ l implying that initial values

are not that different from those seen in the Heart

Protection Study (4). Patients randomised to 80 mg

simvastatin achieved a LDL-C of 2.11 mmol ⁄ l, an

extra 0.39 mmol ⁄ l reduction (16%) (5). The primary

end-point of fatal and non-fatal myocardial infarction

or stroke and added cardiac procedures resulted in a

non-significant 6% reduction in major vascular events

(p = 0.10) and 3.5% in cardiac events (p = 0.23). A

review of the other trials of low-dose vs. high-dose

statin including Treating to new Targets (10 mg vs.

80 mg atorvastatin; 0.60 mmol ⁄ l difference) (6) and

the Incremental Decrease in End Points Through

Aggressive Lipid Lowering study (20 mg simvastatin

vs. 80 mg atorvastatin; 0.50 mmol ⁄ l difference) (7) in

chronic coronary disease shows sig-

nificant reductions in the major vas-

cular events (TnT and IDEAL) but

differ in effects on fatal and non-fatal

cardiac events (TnT but not IDEAL)

(Figure 1).

The SEARCH trial raises the ques-

tions about the safety as well as the

efficacy of high dose simvastatin

treatment. Higher doses of statins

are always associated with greater

side effects (8). The use of sim-

vastatin 80 mg in SEARCH was

associated with a 25-fold increase

in myopathy ⁄ rhabdomyolysis defined

as alanine transaminase · 1.7 base-

line and creatine kinase (CK) · 5

baseline (or > 750 IU ⁄ l) (9). Using

the traditional definition of

CK · 10, simvastatin 80 mg caused

a fivefold increase in rhabdomyolysis

(0.9% vs. 0.2%). The discrepancy with the results

achieved in the TnT and IDEAL trials is notable, as

there atorvastatin 80 mg was associated with a far

lower incidence of, primarily hepatic, side effects (10,

Figure 2) although The SEARCH trial data were pre-

sented briefly allied with a revised meta-analysis of

statin trials with an emphasis that ‘lower = better’

(5). A 0.55 mmol ⁄ l extra reduction in LDL-C was

associated with an extra 13% reduction in vascular

events consistent with the previously demonstrated

22% reduction in vascular events shown in the origi-

nal analysis of statin vs. placebo (11). Given that

two-thirds of the titration trials in chronic coronary

disease, as opposed to acute coronary syndromes

(12), have been negative on the primary outcomes

and that it requires a meta-analysis of > 20,000–

100,000 patients to show a significant difference; the

implication for chronic coronary disease is only in

those patients at higher risk even within the estab-

lished coronary heart disease (CHD) population that

would benefit from additional LDL-C reduction and

then only if the therapy produces a large additional

LDL-C reduction. Only ezetimibe offers a substantial

extra reduction in LDL-C above statins, but it has

not demonstrated any benefit in a clinical trial to

date, so its use is controversial (13,14). Thus contrary

to the spin ‘lower may not be better’ in a practical

sense, as large numbers would need to be treated to

November 2008 saw the release of the last words in car-

diovascular prevention so far as statins are concerned.

Two major trials were presented at the American Heart

Association in New Orleans – the Study of the Effective-

ness of Additional Reduction in Cholesterol and Homocy-

steine with Simvastatin and Folic Acid ⁄ Vitamin B12

(SEARCH) study in secondary prevention of low-dose vs.

high-dose simvastatin (1) and the Justification for the Use

of Statins in Primary Prevention: an Intervention Trial

Evaluating Rosuvastatin (JUPITER) trial in primary pre-

vention of patients with moderate lipid levels and an ele-

vated C-reactive protein (2). Unfortunately, both trials

have been confounded by the spin attached to them. Their

implementation will be a challenge in the light of the

financial constraints, operating within health services fol-

lowing the crash of 2008.

PERSPECT IVE

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 685–688doi: 10.1111/j.1742-1241.2009.02032.x 685

The

implications of

SEARCH for

the UK NICE

guidelines are

devastating

show clear benefits above baseline therapy with sim-

vastatin 40 mg. The implications of SEARCH for the

National Institute for Health and Clinical Excellence

(NICE) guidelines for modification of hyperlipida-

emia in the UK are devastating (15). High-dose

simvastatin is both ineffective and toxic using a

20 fi 80 mg (�10–12%), let alone the 40 fi 80 mg

titration (7%; 0.34 mmol ⁄ l) (16) recommended as

the basis of the guideline. The commonly used dose

of atorvastatin 40 mg (9%; 0.42 mmol ⁄ l) would have

minimal extra benefit based on the results of

SEARCH. Only atorvastatin 80 mg (12%;

0.58 mmol ⁄ l) or rosuvastatin 20 mg (13%;

0.59 mmol ⁄ l) and better 40 mg (16%; 0.84 mmol ⁄ l)

are likely to deliver the necessary > 0.5 mmol ⁄ l extra

LDL-C reduction required to show clear benefits.

A subtler approach to implementation would

invoke risk stratification within secondary prevention

populations, so that patients with acute coronary

syndromes and patients with diabetes or high resid-

ual LDL-C would receive more aggressive treatment.

This initial part of this statement is recommended by

NICE (15). The second awaits confirmation from

meta-analysis of the titration trials but is plausible.

To achieve the extra benefit, the titration form sim-

vastatin 40 mg has to be maximal doses of other sta-

tin rather than to any fixed target with the aim being

a further > 0.5 mmol ⁄ l reduction in LDL-C.

There has long been controversy in primary pre-

vention as to whether statins were capable of reduc-

ing mortality and showing benefits in women as

opposed to men. Neither the West of Scotland Coro-

nary Prevention Study (WOSCOPS) (17) nor the Air

Force Texas Coronary Atheroma Prevention Study

(AF-TexCAPS) (18) showed any benefit on these

end-points, as there were no women in WOSCOPS

and the risk was too low in both trials to show a

mortality difference. However, meta-analysis of all

types of statin trials did show likely benefits (11). It

was noted in a post hoc analysis that a secondary

stratification of the AF-TexCAPS study, where the

primary stratification was the presence of a low

HDL-C, showed that patients with a C-reactive pro-

tein > 1.6 mg ⁄ dl showed significant benefit unlike

patients with CRP < 1.6 mg ⁄ dl (19). The JUPITER

study was designed to investigate the effects of rosu-

vastatin 20 mg vs. placebo in 17,000 primary preven-

tion patients with elevated CRP (20,21). During the

recruitment phase, 50% of patients were rejected for

a LDL-C above the recruitment criterion or for a

CRP < 2 mg ⁄ dl2. Elevated CRP is associated with

excess atheroma, elevated visceral fat, and in JUPI-

TER 41% of patients had the National Cholesterol

Education Program defined metabolic syndrome.

The prevalence of smoking was low at 16%, so the

cause of the elevated CRP is unclear in many cases.

The trial was terminated early after 2 years with a

50% (1.4 mmol ⁄ l) reduction in LDL-C, 37% in CRP

and a 44% reduction in major vascular events and a

20% reduction in total mortality although given

strict adjudication criteria, many likely cardiovascular

deaths were not counted as such. In women, a 46%

reduction in vascular events was demonstrated. The

spin was of overwhelming effectiveness in a low-risk

population using a new marker of CVD risk. This is

not true. The JUPITER trial was stated to be a low-

risk population, but calculation of Framingham risk

(including stroke) shows a 10-year risk of 17.7%

indicating that the intermediate risk further increased

3

TnT-Lo

IDEAL-Lo

IDEAL-Hi

SEARCH-Lo

SEARCH-Hi

TnT-Hi2.5

2

1.5In

cide

nce

(%)

1

0.5

0ALT 3 x ULN (%) CK 10 x ULN (%)

Figure 1 Comparison of the efficacy of low (lo) vs. high

(hi) dose statin trials in chronic coronary disease on

LDL-C and major vascular events

3

TnT-Lo

IDEAL-Lo

IDEAL-Hi

SEARCH-Lo p = 0.02

p < 0.001

p = 0.10

SEARCH-Hi

TnT-Hi

2.5

3.5

4.5

4

2

1.5

1

0.5

0LDL-C (mmol/L) Event rate (%)

Figure 2 Comparison of the safety in the low (lo) vs. high

(hi) dose statin trials in chronic coronary disease using

drug discontinuation criteria: alanine transaminase (ALT)

3 · upper limit of normal (ULN) and creatine kinase (CK)

10 · upper limit of normal

In the USA,

JUPITER will

promote the

profile of CRP

as a stratifying

risk marker

686 Perspective

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 685–688

by the presence of an elevated CRP (and other risk

factors e.g. metabolic syndrome) possibly implying

an overall risk about 20–25% per decade. A close

review of WOSCOPS shows an early reduction in

mortality that attenuates later in the trial and it is

known that trials, which stopped early, show an

overly favourable profile (22). This was clearly seen

in the discrepancy in the highly positive results that

were seen with atorvastatin 10 mg in primary

prevention patients with diabetes in the Collaborative

Atorvastatin Diabetes Study (23), where a 42%

reduction in fatal and non-fatal cardiac events was

shown with a 35% LDL-C reduction after 3 years in

contrast to the Atorvastatin Study for Prevention of

Coronary Heart Disease Endpoints in Non-Insulin-

Dependent Diabetes Mellitus (ASPEN) study of simi-

lar design where the same dose showed a non-signifi-

cant 15% reduction in the same end-point despite a

similar LDL-C reduction after 5 years (24).

So what are the implications of JUPITER? In the

USA, it will promote the profile of CRP as a stratifying

risk marker. However, other methods of risk stratifi-

cation exist ranging from the simple such as family

history of CHD (25) or even house price (26) to bio-

markers such as CRP, lipoprotein-associated phos-

pholipase A2 (27) and asymmetric dimethylarginine

(28). Other methods commonly used that detect ath-

erosclerosis include carotid intima-media thickness

and coronary calcium score (29). There is no evidence

for any of these being superior to any other. Although

JUPITER validates the LDL-C < 2 mmol ⁄ l target

advocated in the Joint British Societies guidelines

(30), and the number needed to treat (NNT) is favour-

able at 125 ⁄ year of treatment, financially this treatment

is not cost-effective compared with off-patent simvast-

atin 40 mg delivering a 1.0–1.3 mmol ⁄ l reduction in

LDL-C. The UK NICE guidelines recommend treat-

ment of all primary prevention patients with 40 mg

simvastatin and no measurement of lipids afterwards.

This approach is undoubtedly cheap (31). The philo-

sophical question fudged in the NICE guidelines is if

both aspirin and statins need no efficacy monitoring

then why measure blood pressure after treatment?

This is the essence of poly-pill concept (32). If on the

other hand risk-based methods are used, then inter-

vention should ideally be proportional to underlying

risk – the concept underlying JUPITER. The concept

of a risk-adjusted primary prevention strategy based

on the use of generic statin for low-risk patients and

rosuvastatin for high-risk patients has never been

modelled in comparison with a fixed treatment strat-

egy but is likely to be more expensive than a blanket

treatment policy.

So where does CVD risk management stand today?

It all depends on how you want to spend your

money. The cheapest solution is blanket therapy to

reduce risk by a fixed proportion – the simvastatin

40 mg ‘fire and forget’ model. The more sophisti-

cated approach of risk-based management titrates

therapies to underlying risk. The current NICE

guidelines are a mix of the two, while the US guide-

lines risk stratify at all levels (33) and the European

guidelines following a mixed approach (34). A review

of the secondary prevention trials suggests that only

an extra 0.5 mmol ⁄ l reduction will show benefits

within the 200 ⁄ year NNT. This suggests that any

switch of therapy from simvastatin 40 mg to ator-

vastatin 40 mg would be ineffective and that only

atorvastatin 80 mg or rosuvastatin 40 mg would be

effective. Virtually nobody does this in the UK or

anywhere else. Indeed although the evidence base is

well known, 58% patients in secondary prevention

do not attain previous LDL-C targets of 3 mmol ⁄ l(35); let alone the current ones and the situation in

primary prevention is worse with only 40% of high-

risk patients on any statin therapy (36). The implica-

tions of EuroASPIRE are depressing in that, despite

the evidence, only an ultra-simple approach seems to

have any promise for wide scale implementation.

Disclosure

Dr Wierzbicki has received grant support, lecture

honoraria and travel grants from Abbott, AstraZene-

ca, Fournier-Solvay, GlaxoSmithKline, Merck kGA,

Merck-Sharp and Dohme, Pfizer, sanofi-aventis and

Takeda pharmaceuticals. Dr Wierzbicki was a mem-

ber of the technology appraisal committee for eze-

timibe at the National Institute of Health and

Clinical Excellence.

A. S. Wierzbicki DM, DPhil, FRCPath, FAHAConsultant in Metabolic Medicine

and Chemical Pathology,St. Thomas’ Hospital,

London SE 1 7EH, UKEmail: anthony.wierzbicki@kcl.ac.uk

References1 Nainggolan L. SEARCH Me: Null Trial ‘‘Morphed’’ into Positive

Meta-Analysis. TheHeart org, 2008. http://www.theheart.org/article/

917661.do (accessed January 2009).

2 Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent

vascular events in men and women with elevated C-reactive pro-

tein. N Engl J Med 2008; 359: 2195–207. Published online,

doi:NEJMoa0807646 [pii];10.1056/NEJMoa0807646 [doi].

3 Bowman L, Armitage J, Bulbulia R et al. Study of the effectiveness

of additional reductions in cholesterol and homocysteine

(SEARCH): characteristics of a randomized trial among 12064

myocardial infarction survivors. Am Heart J 2007; 154: 815–23,

823: published online, doi:S0002-8703(07)00533-9 [pii];10.1016/

j.ahj.2007.06.034 [doi].

The cheapest

solution is the

simvastatin

40 mg ‘fire and

forget’ model

Perspective 687

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 685–688

4 MRC ⁄ BHF Heart Protection Study Investigators. MRC ⁄ BHF Heart

Protection Study of antioxidant vitamin supplementation in

20,536 high-risk individuals: a randomised placebo-controlled trial.

Lancet 2002; 360: 23–33.

5 Clinical Trials Service Unit. Study of the Effectiveness of Additional

Reductions in Cholesterol and Homocysteine (SEARCH). Clinical Tri-

als Service Unit University of Oxford, 2008. http://www.searchinfo.

org/ (accessed January 2009).

6 LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering

with atorvastatin in patients with stable coronary disease. N Engl J

Med 2005; 352: 1425–35.

7 Pedersen TR, Faergeman O, Kastelein JJ et al. High-dose atorvasta-

tin vs usual-dose simvastatin for secondary prevention after myo-

cardial infarction: the IDEAL study: a randomized controlled trial.

JAMA 2005; 294: 2437–45.

8 Silva M, Matthews ML, Jarvis C et al. Meta-analysis of drug-

induced adverse events associated with intensive-dose statin ther-

apy. Clin Ther 2007; 29: 253–60.

9 Link E, Parish S, Armitage J et al. SLCO1B1 variants and statin-

induced myopathy – a genomewide study. N Engl J Med 2008;

359: 789–99.

10 Waters DD. Safety of high-dose atorvastatin therapy. Am J Cardiol

2005; 96: 69F–75F.

11 Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cho-

lesterol-lowering treatment: prospective meta-analysis of data from

90,056 participants in 14 randomised trials of statins. Lancet 2005;

366: 1267–78.

12 Cannon CP, Steinberg BA, Murphy SA et al. Meta-analysis of car-

diovascular outcomes trials comparing intensive versus moderate

statin therapy. J Am Coll Cardiol 2006; 48: 438–45.

13 Rossebo AB, Pedersen TR, Boman K et al. Intensive lipid lowering

with simvastatin and ezetimibe in aortic stenosis. N Engl J Med

2008; 359: 1343–56. Published online, doi:NEJMoa0804602

[pii];10.1056/NEJMoa0804602 [doi].

14 Wierzbicki AS. Muddy waters: more stormy SEAS for ezetimibe.

Int J Clin Pract 2008; 62: 1470–3.

15 National Institute for Health and Clinical Excellence. Lipid Modifi-

cation. London: National Institute for Health and Clinical Excel-

lence, 2008. 17 June. Report No.: CG67.

16 Jones PH, Davidson MH, Stein EA et al. Comparison of the effi-

cacy and safety of rosuvastatin versus atorvastatin, simvastatin, and

pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003; 92:

152–60.

17 Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart

disease with pravastatin in men with hypercholesterolemia. West

of Scotland Coronary Prevention Study Group. N Engl J Med

1995; 333: 1301–7.

18 Downs JR, Clearfield M, Weis S et al. Primary prevention of acute

coronary events with lovastatin in men and women with average

cholesterol levels: results of AFCAPS ⁄ TexCAPS. Air Force ⁄ Texas

Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:

1615–22.

19 Ridker PM, Rifai N, Clearfield M et al. Measurement of C-reactive

protein for the targeting of statin therapy in the primary preven-

tion of acute coronary events. N Engl J Med 2001; 344: 1959–65.

20 Ridker PM. Rosuvastatin in the primary prevention of cardiovas-

cular disease among patients with low levels of low-density lipo-

protein cholesterol and elevated high-sensitivity C-reactive protein:

rationale and design of the JUPITER trial. Circulation 2003; 108:

2292–7. Published online, doi:10.1161/01.CIR.0000100688.17280.E6

[doi]; 108/19/2292 [pii].

21 Ridker PM, Fonseca FA, Genest J et al. Baseline characteristics of

participants in the JUPITER trial, a randomized placebo-controlled

primary prevention trial of statin therapy among individuals with

low low-density lipoprotein cholesterol and elevated high-sensitiv-

ity C-reactive protein. Am J Cardiol 2007; 100: 1659–64.

22 Montori VM, Devereaux PJ, Adhikari NK et al. Randomized trials

stopped early for benefit: a systematic review. JAMA 2005; 294:

2203–9. Published online, doi:294/17/2203 [pii]; 10.1001/jama.

294.17.2203 [doi].

23 Colhoun HM, Betteridge DJ, Durrington PN et al. Primary pre-

vention of cardiovascular disease with atorvastatin in type 2 diabe-

tes in the Collaborative Atorvastatin Diabetes Study (CARDS):

multicentre randomised placebo-controlled trial. Lancet 2004; 364:

685–96.

24 Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety

of atorvastatin in the prevention of cardiovascular end points in

subjects with type 2 diabetes: the Atorvastatin Study for Prevention

of Coronary Heart Disease Endpoints in Non-Insulin-Dependent

Diabetes Mellitus (ASPEN). Diabetes Care 2006; 29: 1478–85.

25 Mainous AG III, Koopman RJ, Diaz VA et al. A coronary heart

disease risk score based on patient-reported information. Am J

Cardiol 2007; 99: 1236–41. Published online, doi:S0002-9149(07)

00146-4 [pii]; 10.1016/j.amjcard.2006.12.035 [doi].

26 Cozier YC, Palmer JR, Horton NJ et al. Relation between neigh-

borhood median housing value and hypertension risk among black

women in the United States. Am J Public Health 2007; 97: 718–24.

Published online, doi:AJPH.2005.074740 [pii]; 10.2105/AJPH.2005.

074740 [doi].

27 O’Donoghue M, Morrow DA, Sabatine MS et al. Lipoprotein-asso-

ciated phospholipase A2 and its association with cardiovascular

outcomes in patients with acute coronary syndromes in the

PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and

Infection Therapy-Thrombolysis In Myocardial Infarction) trial.

Circulation 2006; 113: 1745–52.

28 Boger RH. Asymmetric dimethylarginine (ADMA): a novel risk

marker in cardiovascular medicine and beyond. Ann Med

2006; 38: 126–36. Published online, doi:X68476T031657H96 [pii];

10.1080/07853890500472151 [doi].

29 Wierzbicki AS. Surrogate markers, atherosclerosis and cardiovascu-

lar disease prevention. Int J Clin Pract 2008; 62: 981–7.

30 British Cardiac Society, British Hypertension Society, Diabetes UK

et al. JBS 2: the Joint British Societies’ guidelines for prevention of

cardiovascular disease in clinical practice. Heart 2005; 91 (Suppl.

V): v1–52.

31 Reynolds TM, Mardani A, Twomey PJ, Wierzbicki AS. Targeted

versus global approaches to the management of hypercholesterola-

emia. Perspect Public Health 2008; 128: 248–54.

32 Wald NJ, Law MR. A strategy to reduce cardiovascular disease by

more than 80%. BMJ 2003; 326: 1419. Published online,

doi:10.1136/bmj.326.7404.1419 [doi]; 326/7404/1419 [pii].

33 Expert Panel on Detection EAToHBCIAATPI. Executive summary

of the third report of the National Cholesterol Education Program

(NCEP). JAMA 2001; 285: 2486–97.

34 Graham I, Atar D, Borch-Johnsen K et al. European guidelines on

cardiovascular disease prevention in clinical practice: full text.

Fourth Joint Task Force of the European Society of Cardiology

and other societies on cardiovascular disease prevention in clinical

practice (constituted by representatives of nine societies and by

invited experts). Eur J Cardiovasc Prev Rehabil 2007; 14 (Suppl. 2):

S1–113.

35 Kotseva K, Stagmo M, De BD et al. Treatment potential for cho-

lesterol management in patients with coronary heart disease in 15

European countries: findings from the EUROASPIRE II survey.

Atherosclerosis 2008; 197: 710–7. Published online, doi:S0021-

9150(07)00448-0 [pii]; 10.1016/j.atherosclerosis.2007.07.004 [doi].

36 Wood D, Ryden L. EUROASPIRE III: Lifestyle, Risk Factor and

Therapeutic Management in People at High Risk of Developing

Cardiovascular Disease From 12 European Regions. European

Society of Cardiology Congress, 2008. http://www.escardio.org/

congresses/esc2008/congress-reports/Pages/4480-4481-wood-ryden.

aspx (accessed January 2009).

688 Perspective

ª 2009 Blackwell Publishing Ltd Int J Clin Pract, May 2009, 63, 5, 685–688