Practice makes perfect: reflections on a primary care treatment-to-target study

should be aware of their own protocols and audit

their usage probably through a local thrombosis com-

mittee. It is also important to offer patients and ⁄ or

their families or carers verbal and written information

on the signs and symptoms of DVT and PE, and the

importance of seeking medical help and who to con-

tact if DVT, PE or another adverse event is suspected.

The message is that further research is needed.

However, at the present time, it seems appropriate to

individually risk assess all admitted psychiatric

patients for VTE and bleeding risk, and consider

physical restraint and the use of antipsychotic ther-

apy as additional risk factors mandating prophylaxis.

Disclosures

GS and OH have no disclosures. SN is a medical

director for Lifeblood: the thrombosis charity and

has lectured for Pfizer and Leo Pharma.

G. Stansby,1 S. Noble,2 O. Howes3

1Freeman Hospital and Newcastle University,Newcastle upon Tyne, UK

2Department of Palliative Medicine, Cardiff, UK3Institute of Psychiatry, Kings College, London, UK

Email: [email protected]

References1 Department of Health. Report of the Independent Expert Working

Group on the Prevention of Venous Thromboembolism (VTE) in

Hospitalised Patients. 2007 http://www.dh.gov.uk/prod_consum_

dh/groups/dh_digitalassets/documents/digitalasset/dh_073950.pdf

(accessed May 2010).

2 Hunt BJ. Awareness and politics of venous thromboembolism in the

United Kingdom. Arterioscler Thromb Vasc Biol 2008; 28: 398–9.

3 NICE Clinical Guideline 92. Reducing the Risk of Venous Thrombo-

embolism (Deep Vein Thrombosis and Pulmonary Embolism) in

Patients Admitted to Hospital. http://guidance.nice.org.uk/CG92


4 Hill J, Treasure T, National Clinical Guideline Centre for Acute

and Chronic Conditions. Reducing the risk of venous thromboem-

bolism in patients admitted to hospital: summary of NICE guid-

ance. BMJ 2010; 27: 340.

5 Department of Health. Using the Commissioning for Quality and

Innovation (CQUIN) Payment Framework – an Addendum to

the 2008 Policy Guidance for 2010 ⁄ 11. http://www.dh.gov.uk/dr_

consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_10431.

pdf (accessed May 2010).

6 Department of Health. Risk Assessment for Venous Thromboem-

bolism (VTE). http://www.dh.gov.uk/prod_consum_dh/groups/

dh_digitalassets/@dh/@en/documents/digitalasset/dh_088216.pdf


7 Dietrich-Muszalska A, Rabe-Jabłonska J, Olas B. The effects of the

second generation antipsychotics and a typical neuroleptic on col-

lagen-induced platelet aggregation in vitro. World J Biol Psychiatry

2010; 11(2 Pt 2): 293–9.

8 Thomassen R, Vandenbroucke JP, Rosendaal FR. Antipsychotic

medication and venous thrombosis. Br J Psychiatry 2001; 179: 63–

6.

9 Singh G, Wahi S. Pulmonary embolism in the ECT patient: a case

report and discussion. Gen Hosp Psychiatry 2008; 30: 87–9.

10 Dickson BC, Pollanen MS. Fatal thromboembolic disease: a risk in

physically restrained psychiatric patients. J Forensic Leg Med 2009;

16: 284–6.

11 Laursen SB, Jensen TN, Bolwig T, Olsen NV. Deep venous throm-

bosis and pulmonary embolism following physical restraint. Acta

Psychiatr Scand 2005; 111: 324–7.

12 Hewer W, Kauder E, Vierling P. Fatal pulmonary embolism

following antipsychotic treatment and physical restraint. Phar-

macopsychiatry 2009; 42: 206–8.

doi: 10.1111/j.1742-1241.2010.02435.x

ED ITORIAL

Practice makes perfect: reflections on a primary caretreatment-to-target study

The pharmaceutical industry is very fond of treat-

ment-to-target studies. They are easy to do, primary

care friendly, always give supposedly large probabili-

ties of having had a real effect, are cheap and are

easily marketable. All of these are also reasons why

they should not be performed.

The IN-PRACTICE study is a typical example of

this type (1). It purports to suggest a clinical signifi-

cance to an investigation of the efficacy of a simvast-

atin–ezetimibe combination compared with dose

titration of rosuvastatin or atorvastatin in achieving

the UK targets for prevention in patients not achiev-

ing ‘target’ on 40 mg simvastatin. Like many of these

studies it is large – 786 patients, demonstrates very

high rates of target attainment with its chosen com-

pound (70% for simvastatin–ezetimibe vs. 33% for

atorvastatin and 14% for rosuvastatin) and gives the

message that treatment with simvastatin–ezetimibe

should be the first choice for patients not achieving

target on the generic first-line regime.

So what is wrong with it? The study design is rea-

sonable with a 6-week run-in on simvastatin, 6-week

treatment period, rigorous with regards to protocol,

and on entry, the three groups of 250 patients were

reasonably well-matched. The flaws begin with the

assumptions in its design for a UK study. It is based

Linked Comment: McCormack et al. Int J Clin Pract 2010; 64: 1052–61.

Treatment-to-

target studies

are often

misleading

1006 Editorials

ª 2010 Blackwell Publishing Ltd Int J Clin Pract, July 2010, 64, 8, 997–1008

on the Joint British Societies guidelines (JBS-2; 2005)

(2) preferred numbers rather than the JBS-2 audit

standards [total cholesterol (TC) <5 mmol ⁄ l and

LDL-C <3 mmol ⁄ l. The actual targets used in the UK

are those of the National Institute for Health and

Clinical Excellence (NICE; 2007–2009), which are

mandated by the UK Government and which are cru-

dely assessed through the National Health Service

Quality Outcomes Framework using a TC

<5 mmol ⁄ l. The JBS-2 guidelines have been criticised

especially in regards to non-evidence-based state-

ments about primary prevention (3). They also state

that the target is TC <4 mmol ⁄ l and LDL-C

<2 mmol ⁄ l, but this study uses the commonly mis-

assumed ‘or’ formulation. The NICE hyperlipidaemia

guideline (4), promulgated as stated after the com-

mencement of this study, states that secondary pre-

vention patients should be started on 40 mg of

simvastatin, and if they do not attain a TC

<4 mmol ⁄ l or a <LDL-C <2 mmol ⁄ l treatment

should be intensified. There is no target figure. This

statement is controversial and may be modified in

2010 in light of concerns about simvastatin 80 mg

(5,6).

Similarly for primary prevention, no target is spec-

ified by NICE and the treatment is recommended

only with simvastatin 40 mg with no lipid measure-

ment except possibly for monitoring compliance. For

type 2 diabetes, NICE states that treatment should

aim for a TC <4 mmol ⁄ l or a LDL-C <2 mmol ⁄ l if

simvastatin treatment was unsuccessful and patients

have stable well-controlled diabetes (7). The NICE

technology appraisal for ezetimibe is specific in sug-

gesting the requirement to titrate statin doses fully

before considering the use of ezetimibe (8).

The IN-PRACTICE patient population includes

50–52% without established cardiovascular disease or

diabetes. These are all randomised in a similar man-

ner to secondary prevention or diabetes patients and

predictably achieve greater target attainment with

more powerful lipid-reducing agents. However, the

cost-effectiveness of such an approach is highly dubi-

ous given on-patent medications and is likely if

implemented simply to cause excess side-effects with

statins for minimal event reduction – a problem

recently clearly demonstrated in an analogous pri-

mary prevention setting with aspirin – a very cheap

drug (9). Risk assessment is a crude tool, and to

demonstrate significant benefit in primary preven-

tion, clinical trialists have to resort to methods to

increase event rates. Thus, the primary prevention

Justification for the Use of Statins in Primary

Prevention: an Intervention Trial Evaluating

Rosuvastatin (JUPITER) study recruited patients at

intermediate risk with an added inflammation factor

– C-reactive protein (CRP) (10). In its design, it was

noted that in Air Force-Texas Coronary Artery

Prevention Study (AF-TexCAPS) that served as its

antecedent, the intermediate risk group with low

CRP levels had virtually no events (11). Thus, inten-

sified treatment in Framingham algorithm risk

assessed that primary prevention is probably not cost

or clinical event effective. Whether this is true of all

patients in that group is open to debate, and numer-

ous methods of further stratifying risk have been

proposed but many remain to be fully validated (12).

In secondary prevention and diabetes, 50% of

patients achieves a target of TC <4 or LDL <2 mmol ⁄ lwith simvastatin 40 mg. This is exactly as expected in

this population and is noted in the initial recruitment

of 1738 patients to IN-PRACTICE of which 786 pro-

ceed to randomisation. Predictably, targets are better

attained with simvastatin–ezetimibe than atorvastatin

40 mg or not surprisingly rosuvastatin 5–10 mg. The

rosuvastatin data in IN-PRACTICE are completely at

odds with dose comparison studies (13) and reflect

the very low doses used and the extreme emphasis on

titration from a minimal initial dose. Many rosuvast-

atin studies have since initiated the treatment at far

higher doses including the use of 20 mg in the

endpoint JUPITER study (10) and 40 mg in primary

prevention in the carotid intima media thickness

study – Measuring Effects on Intima-Media Thick-

ness: an Evaluation of Rosuvastatin (METEOR) (14).

The IN-PRACTICE rosuvastatin results are incredible

and should be discounted. Despite a similar regula-

tory recommendation for atorvastatin, this was not

followed for that drug, and so there was a design fail-

ure in this trial (15). The poor target attainment for

the commonly used atorvastatin 40 mg dose simply

confirms that adequate dose titration from simvasta-

tin 40 mg to achieve recommended targets if these

are assumed to be TC <4 mmol ⁄ l or LDL-C

<2 mmol ⁄ l which correspond to levels associated

with significant event benefits, then titration ⁄ switch

ought be to 80 mg atorvastatin – the evidence-based

dose (16). This increment is cost-effective over sim-

vastatin 40 mg and will dominate the health economy

once atorvastatin is off patent in 2010–2011. There is

no role for 40 mg atorvastatin.

The study uses simvastatin–ezetimibe in a co-for-

mulation. In UK practice, this is not cost-effective, as

the single drugs are considerably cheaper than the

combination. In addition, though simvastatin and

ezetimbe are cost-effective in health economic mod-

els (8), the current trial evidence from the Ezetimibe

and Simvastatin in Hypercholesterolemia Enhances

Atherosclerosis Regression (ENHANCE) (17) and the

Simvastatin–Ezetimibe and Aortic Stenosis (SEAS)

(18) studies suggest minimal benefit on surrogate

Editorials 1007


markers or cardiovascular endpoints over the statin

component alone. There are acknowledged methodo-

logical problems in both trials (19,20), but as yet

ezetimibe cannot be recommended as a first-line

agent. Thus, this part of the study is again open to

question in terms of its practical conclusions.

The study is short-term 6 weeks, and though the

adherence rate is 95%, this represents a clinical

trial supervised group preselected for compliant

behaviour. In reality, compliance in cardiovascular

prevention deteriorates significantly with time and

patient-perceived lower risk of future events. In reg-

istry studies, 53% of cardiovascular prevention

patients discontinue statin therapy after 2 years (21).

As lipid-lowering therapies are only really effective

over 3- to 5-year time scales, the IN-PRACTICE

study is no guide to the critical question of the long-

term acceptability of treatment.

So what does the IN-PRACTICE study tell us? The

answer is simply not to do studies such as this which

once IN-THEORY seemed a good idea. Design stud-

ies with realistic scenarios and with real doses used

in clinically evidence-based protocols and remember

to consider the implications for clinical endpoints.

Always remember that motor industry gave us the

Porsche 911, the Aston Martin DB5, the Jaguar

E-type but also the Ford Edsel, the Lada and the

incomparable Trabant.

Disclosure

Dr Wierzbicki has received grant support, lecture

honoraria and travel grants from Abbott, Fournier-

Solvay, GlaxoSmithKline, Merck kGA, Merck-Sharp

& Dohme, Pfizer, Sanofi-Aventis and Takeda phar-

maceuticals. Dr Wierzbicki is a member of the tech-

nology appraisal panels and was a member of the

familial hypercholesterolaemia guideline development

group and the technology appraisal committee for

ezetimibe at the National Institute of Health and

Clinical Excellence.

A. S. WierzbickiGuy’s & St Thomas’ Hospitals, London, UK

Email: [email protected]

References1 McCormack T, Harvey P, Gaunt R et al. Incremental cholesterol

reduction with simvastatin-ezetimibe, atorvastatin and rosuvasta-

tin in UK general practice (IN-PRACTICE). Randomised con-

trolled trial of achievement of Joint British Societies (JBS-2)

cholesterol targets. Int J Clin Pract 2010; 64: 1052–61.

2 British Cardiac Society, British Hypertension Society, Diabetes UK

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

4): 51–52.

3 Minhas R. Eminence-based guidelines: a quality assessment of the

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

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Excellence, 2008, Report No.: CG67.

5 Wierzbicki AS. SEARCHing for JUPITER: starry eyed optimism is

not warranted. Int J Clin Pract 2009; 63: 685–8.

6 Food & Drug Administration. FDA Drug Safety Communication:

Ongoing Safety Review of High-Dose Zocor (Simvastatin) and

Increased Risk of Muscle Injury. Washington DC, USA: Food &

Drug Administration, 2010.

7 National Institute for Health and Clinical Excellence. Type 2 Diabe-

tes: The Management of Type 2 Diabetes (Update). London: National

Institute for Health and Clinical Excellence, 2008, Report No.:

CG66.

8 National Institute for Health and Clinical Excellence. Ezetimibe for

the Treatment of Primary (Heterozygous-Familial and non-Familial)

Hypercholesterolaemia: Technology Appraisal 132. London: Her Maj-

esty’s Stationery Office, 2007.

9 Fowkes FG, Price JF, Stewart MC et al. Aspirin for prevention of

cardiovascular events in a general population screened for a low

ankle brachial index: a randomized controlled trial. JAMA 2010;

303: 841–8.

10 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.

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

protein for the targeting of statin therapy in the primary prevention

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

12 Wierzbicki AS. Surrogate markers, atherosclerosis and cardiovascu-

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

13 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.

14 Crouse JR III, Raichlen JS, Riley WA et al. Effect of rosuvastatin

on progression of carotid intima-media thickness in low-risk indi-

viduals with subclinical atherosclerosis: the METEOR Trial. JAMA

2007; 297: 1344–53.

15 Medicines & Health Regulatory Agency. Statins: interactions

and updated advice for atorvastatin. Drug Safety Update 2008; 1:

2–5.

16 Ara R, Rafia R, Ward SE et al. Are intensive lipid-lowering regi-

mens an optimal economic strategy in patients with ACS? an acute

and chronic perspective. Expert Rev Pharmacoecon Outcomes Res

2009; 9: 423–33.

17 Kastelein JJ, Akdim F, Stroes ES et al. Simvastatin with or without

ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;

358: 1431–43.

18 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.

19 Viljoen A, Wierzbicki AS. Enhanced LDL-C reduction: lower is

better. Does it matter how? Int J Clin Pract 2008; 62: 518–20.

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

Int J Clin Pract 2008; 62: 1470–3.

21 Penning-van Beest FJ, Termorshuizen F, Goettsch WG et al.

Adherence to evidence-based statin guidelines reduces the risk of

hospitalizations for acute myocardial infarction by 40%: a cohort

study. Eur Heart J 2007; 28: 154–9.

doi: 10.1111/j.1742-1241.2010.02459.x

1008 Editorials


Documents

Practice makes perfect: reflections on a primary care treatment-to-target study