BMJ  2003;327:1264 (29 November), doi:10.1136/bmj.327.7426.1264

Primary care

Coronary heart disease prevention: insights from modelling incremental cost effectiveness

¹ Department of Public Health and Epidemiology, University of Birmingham, Birmingham B15 2TT

Abstract

Objective To determine which treatments for preventing coronary heart disease should be offered to which patients by assessing their incremental cost effectiveness.

Design Modelling study

Data sources Cost estimates (for NHS) and estimates of effectiveness obtained for aspirin, antihypertensive drugs, statins and clopidogrel.

Data synthesis Treatment effects were assumed to be independent, and cost per coronary event prevented was calculated for treatments individually and in combination across patients at a range of coronary risks.

Results The most cost effective preventive treatments are aspirin, initial antihypertensive treatment (bendrofluazide and atenolol), and intensive antihypertensive treatment (bendrofluazide, atenolol and enalapril), whereas simvastatin and clopidogrel are the least cost effective (cost per coronary event prevented in a patient at 10% coronary risk over five years is £3500 for aspirin, £12 500 for initial antihypertensives, £18 300 for intensive antihypertensives, £60 000 for clopidogrel, and £61 400 for simvastatin). Aspirin in a patient at 5% five year coronary risk costs less than a fifth as much per event prevented (£7900) as simvastatin in a patient at 30% five year risk (£40 800).

Discussion A cost effective prevention strategy would offer aspirin and initial antihypertensive treatment to all patients at greater than 7.5% five year coronary risk before offering statins or clopidogrel to patients at greater than 15% five year coronary risk. Incremental cost effectiveness analysis of treatments produces robust, practical cost effectiveness rankings that can be used to inform treatment guidelines.

Introduction

Preventing coronary heart disease has assumed increasing importance in UK health policy.¹ Several treatments reduce risk of coronary disease, the absolute benefits being proportional to pretreatment risk, and individual patients may be eligible for more than one treatment. It is argued that treatments for lowering blood pressure and cholesterol are equally effective whether or not blood pressure or cholesterol levels exceed arbitrary thresholds.² This means that virtually all patients might benefit from risk lowering treatments.

Given that health service resources are finite, a rational approach to treatment would offer patients treatments in order of their expected cost effectiveness. This requires knowledge of the incremental benefits of risk lowering treatments in relation to their incremental costs. Incremental cost effectiveness analysis provides a means of ranking treatments by calculating the incremental changes in both costs and benefits. This paper presents an incremental cost effectiveness analysis of risk lowering treatments in patients at varying levels of risk. The treatments analysed are aspirin, initial antihypertensive treatment, intensive antihypertensive treatment, a statin, and clopidogrel.

Methods

Costs
Costs are considered from the perspective of the health service and are discounted at 6% per year.³ There are two main components to the costs of long term treatment—follow up costs and prescribing costs.

Follow up costs are based on the cost of two clinic appointments a year with a practice nurse,⁴ and the cost of blood tests. Patients taking thiazide diuretics require annual measurement of serum electrolytes and uric acid. Patients taking statins require annual measurement of serum lipid concentrations and liver function tests.

Prescribing costs include drug⁵ and dispensing costs.⁶ Initial antihypertensive treatment is with bendrofluazide (bendroflumethiazide) 2.5 mg and atenolol 50 mg; further antihypertensive treatment adds enalapril 20 mg to these treatments. Cholesterol lowering is with simvastatin 40 mg. Clopidogrel is given at a dose of 75 mg daily.

Effectiveness
I calculated benefits of treatment as major coronary events (myocardial infarctions, new cases of angina, and cardiac deaths) prevented over five years, with the benefits discounted at 1.5% per annum in keeping with current guidelines from the National Institute for Clinical Excellence.³

In the base case analysis, I calculated cost effectiveness for a patient whose pretreatment five year coronary risk is 10%.⁷ This is the coronary risk of a non-diabetic, non-smoking man aged 62 with blood pressure of 160/98 mm Hg, total serum cholesterol concentration of 6.5 mmol/l, and high density lipoprotein cholesterol concentration of 1.3 mmol/l. Under current guidelines he is eligible for antihypertensive treatment, a statin, and aspirin.⁸

For each intervention, I derived relative risk of coronary heart disease from a recent meta-analysis (see bmj.com for details), and these are shown in column A of table 1. Aspirin also increases the incidence of major bleeding by 0.3% (0.2% to 0.4%) over five years of treatment.⁹ To take account of this, I offset the absolute reduction in coronary risk over five years by 0.3%.

View this table: [in this window] [in a new window]   Table 1 Average costs, effects, and cost effectiveness of preventive treatments in a patient at 10% risk of a coronary event over five years

 

If treatment effects are independent the relative risk with two or more treatments is the product of the relative risk on each treatment. For example, the relative risk of a coronary event with aspirin is 0.72, with a statin is 0.69, and with aspirin and a statin is 0.50 (0.50 = 0.72x0.69).

Average cost effectiveness
I calculated the cost of each intervention over a five year time horizon, and calculated the reduction in absolute coronary risk by subtracting post-treatment risk from pretreatment risk. Post-treatment risk is the product of pretreatment risk and the relative risk with treatment. In the case of aspirin, 0.3% is subtracted from the reduction in absolute coronary risk to take account of major adverse effects. The cost effectiveness ratio (cost per event prevented) is the total cost divided by the reduction in absolute coronary risk.

In a sensitivity analysis I calculated maximum and minimum costs per event prevented for each of the interventions using the upper and lower 95% confidence limits for effectiveness. The average cost effectiveness rankings inform the order in which treatments would be offered in an incremental cost effectiveness analysis. To test the robustness of cost effectiveness rankings, I explored the effects of changes in the costs of interventions and the frequency of adverse effects alongside changed assumptions about effectiveness.

Incremental cost effectiveness
An efficient prevention strategy would offer the most cost effective treatment first, then the next most cost effective treatment, and so on. The incremental cost effectiveness ratio is the additional cost associated with adding each treatment divided by the additional benefit of the treatment. The incremental cost per event prevented is calculated in much the same way as the average cost per event prevented (see bmj.com).

A sensitivity analysis tested the robustness of cost effectiveness ratios by changing assumptions about effectiveness and identifying the threshold costs at which cost effectiveness rankings would change. Since the cost per coronary event prevented decreases as patients' coronary risk increases, I also investigated the cost effectiveness of coronary disease prevention in patients at a range of five year coronary risks.

Results

Average cost effectiveness
In a patient at 10% coronary risk over five years, aspirin is the most cost effective risk lowering treatment (see table 1 and figure). The sensitivity analysis showed that, for simvastatin to be of similar cost effectiveness to intensive antihypertensive treatment, the relative risk with treatment must be at the lower 95% confidence interval and the cost of the drug 65% lower. This is unlikely, as drug prices typically fall by less than 50% when they come off patent. There is a wide degree of uncertainty about the cost effectiveness of clopidogrel, reflecting uncertainty about the relative risk on treatment.

View larger version (23K): [in this window] [in a new window]   Average cost effectiveness of preventive treatments in a patient at 10% risk of a coronary event over five years. (Error bars represent cost per coronary event prevented if effectiveness is at upper and lower 95% confidence limit)

 

Cost effectiveness of initial and intensive antihypertensive treatment is sensitive to increases in the price of drugs. If sufficiently high cost drugs are used (such as for brand name calcium channel blockers) the cost per event prevented with initial antihypertensive drugs is as high as with a statin.

Incremental cost effectiveness of additional treatments
The incremental costs of additional treatments include only additional drug costs and additional laboratory investigations. The incremental effectiveness of additional drugs is also smaller than their effectiveness as initial treatments, because incremental effects act on progressively smaller pretreatment risks.

If a patient at 10% five year coronary risk is given combination treatments in order of their cost effectiveness, the incremental cost per event prevented rises with each additional treatment. Compared with placebo, clopidogrel is more cost effective than simvastatin. However, clopidogrel as a replacement for aspirin provides little additional benefit at substantial extra cost. It is therefore the least cost effective in an incremental analysis. Table 2 shows the incremental costs per event prevented.

View this table: [in this window] [in a new window]   Table 2 Incremental costs of preventive treatments in combination per event avoided in a patient at 10% risk of a coronary event over five years

 

The sensitivity analysis showed that the most favourable assumption for simvastatin is that relative risks for all other treatments are at the upper 95% confidence limit and for simvastatin is at the lower 95% confidence limit. If this is the case, the incremental costs per event prevented are £8700 for aspirin, £18 800 for initial antihypertensive treatment, £243 000 for intensive antihypertensive treatment, £65 800 for simvastatin, and £177 300 for clopidogrel. Even under these assumptions, the price of simvastatin would have to fall by 70%, and the price of clopidogrel by more than 90%, to be of similar cost effectiveness to initial antihypertensive treatment.

Further analysis
Under the base case analysis, the cost effectiveness rankings of all five treatments are the same for any patient with a five year coronary risk greater than 1.5%. The incremental cost per event prevented in a patient at 5% five year coronary risk is £7900 with aspirin and £24 000 with initial antihypertensive treatment. This is less than the incremental cost per event prevented with simvastatin (£40 800) in a patient at 30% five year coronary risk (see bmj.com).

The most extreme assumptions we can make are to assume that relative risk on all treatments is at the upper 95% confidence limit (least effective) and assume that the relative risk with simvastatin is at the lower 95% confidence limit (most effective). Under these assumptions, the cost per event prevented with aspirin in a patient at 7.5% five year risk would be £12 900 and the cost per event prevented with simvastatin in a patient at 15% five year risk would be £13 200.

Discussion

This analysis confirms the poor cost effectiveness of statins and clopidogrel compared with aspirin and antihypertensive treatment,^{10 11} and suggests it is likely to be more cost effective to treat patients at 5% five year coronary risk with aspirin than to prescribe further antihypertensive treatment or statins to patients at 30% five year risk.

Limitations of study
Some of the findings are sensitive to the choice of drug. This is particularly true of the cost effectiveness of initial antihypertensive treatment, where drug prices range from £10 to £290 a year. However, consideration of every possible antihypertensive regimen is beyond the scope of this paper.

The analysis may overestimate the benefits of some interventions. Estimates of the effects of intensive antihypertensive treatment are derived from studies comparing less intensive with more intensive treatment.¹² But the estimate of the benefits of initial antihypertensive treatment include all blood pressure lowering, not just less intensive treatment.¹³ The additional benefits of intensive antihypertensive treatment may therefore be exaggerated.

Apart from major bleeding due to aspirin, the analysis takes no account of adverse effects of treatment. However, major irreversible adverse event rates would have to be 0% with a statin and to exceed 2.5% per five years with aspirin and 1.3% with initial antihypertensive treatment for the statin to be more cost effective than the latter two treatments. Even if all patients who experience adverse effects discontinue treatment but continue to be followed up, this makes no difference to the cost effectiveness rankings.

What is already known on this topic Aspirin, antihypertensive treatment, statins, and clopidogrel are all effective in preventing coronary heart disease These drugs vary in their cost effectiveness, and a rational prevention strategy would offer the most cost effective treatments first What this study adds Most of the benefits of prevention can be achieved with aspirin and antihypertensive treatment at a fraction of the cost of simvastatin or clopidogrel Treating a patient with a five year coronary risk of 7.5% with aspirin and low cost antihypertensives is more cost effective than treating a patient with 30% coronary risk with a statin Clinical guidelines should be informed by analysis of the incremental costs and incremental benefits resulting from each additional treatment

Conclusion
Incremental cost effectiveness analysis of treatments produces robust, practical cost effectiveness rankings. Authors of guidelines should take account of this when making treatment recommendations. If the aim of treatment is to maximise prevention of coronary disease, these results cast doubt on present policy, which emphasises achievement of target blood pressures and the use of statins for people at 15% five year risk of a coronary event.¹⁴ A more efficient prevention strategy would be to offer aspirin and initial antihypertensive treatment to all people at over 7.5% five year coronary risk before offering statins to patients at 30% five year risk. According to national survey data, 87% of men and 56% of women aged over 65 are at over 7.5% five year risk.¹⁵

---

This is an abridged version; the full version is on bmj.com

Editorial by Warburton

Funding: None.

Competing interests: None declared.

Ethical approval: Not applicable.

References

1. Department of Health. Chapter 2: Preventing coronary heart disease in high risk patients. In: National service framework for coronary heart disease. London: DoH, 2000: 1-32.
2. Law MR, Wald NJ. Risk factor thresholds: their existence under scrutiny. BMJ 2002;324: 1570-6.[Free Full Text]
3. National Institute for Clinical Excellence. NICE technical guidance for manufacturers and sponsors on making a submission to a technology appraisal. London: NICE, 2001.
4. Netten A, Curtil L. Unit costs of health and social care 2001. Canterbury: Personal Social Services Research Unit, University of Kent, 2001.
5. British Medical Association, Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMA, RPS, 2002. (No 44.)
6. Prescription Pricing Authority. Drug tariff. London: Stationery Office, 2002.
7. Anderson KM, Wilson PWF, Odell PM, Kannel WB. An updated coronary risk profile. A statement for health professionals. Circulation 1991;83: 356-62.[Free Full Text]
8. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, endorsed by British Diabetic Association. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998;80(suppl 2): S1-29.
9. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of coronary events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002;136: 161-72.[Abstract/Free Full Text]
10. Gaspoz J-M, Coxson PG, Goldman PA, Williams LW, Kuntz KM, Hunink MGM, et al. Cost-effectiveness of aspirin, clopidogrel, or both for secondary prevention coronary heart disease. N Engl J Med 2002;346: 1800-6.[Abstract/Free Full Text]
11. Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al. What role for statins? A review and economic model. Health Technol Assess 1999;3(19): i-iv, 1-91.
12. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;356: 1955-64.[CrossRef][Web of Science][Medline]
13. Gueyffier F, Boutitie F, Boissel JP, Pocock S, Coope J, Cutler J, et al, for the INDANA Investigators. Effect of antihypertensive drug treatment on coronary outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. Ann Intern Med 1997;126: 761-7.[Abstract/Free Full Text]
14. Department of Health. National service framework for coronary heart disease. London: DoH, 2000.
15. Health Survey for England 1998. London: Stationery Office, 2000.

(Accepted October 10, 2003)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

Prevention of coronary heart disease: Statins are even less effective than paper shows

David Taylor, Arnold Jenkins, and Philipp Conradi
BMJ 2004 328: 404. [Extract] [Full Text]

Prevention of coronary heart disease: Is a cure too expensive?

G Alastair Cooke
BMJ 2004 328: 405. [Extract] [Full Text]

Prevention of coronary heart disease: Incremental cost effectiveness raises issues

William C D'Avanzo
BMJ 2004 328: 405. [Extract] [Full Text]

Prevention of coronary heart disease: Data in table 2 could be shown more explicitly for better understanding

Andrea Messori and Benedetta Santarlasci
BMJ 2004 328: 405. [Extract] [Full Text]

Prevention of coronary heart disease: Author's reply

Tom Marshall
BMJ 2004 328: 405-406. [Extract] [Full Text]

Balancing aspirin and statins for heart disease prevention
BMJ 2003 327: 0. [Full Text]

The NHS experiment

Kamran Abbasi
BMJ 2003 327: 0. [Extract] [Full Text] [PDF]

What do we gain from the sixth coronary heart disease drug?

Rebecca N Warburton
BMJ 2003 327: 1237-1238. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Pletcher, M. J., Lazar, L., Bibbins-Domingo, K., Moran, A., Rodondi, N., Coxson, P., Lightwood, J., Williams, L., Goldman, L. (2009). Comparing Impact and Cost-Effectiveness of Primary Prevention Strategies for Lipid-Lowering. ANN INTERN MED 150: 243-254 [Abstract] [Full text]  
• Collins, P., Rosano, G., Casey, C., Daly, C., Gambacciani, M., Hadji, P., Kaaja, R., Mikkola, T., Palacios, S., Preston, R., Simon, T., Stevenson, J., Stramba-Badiale, M. (2007). Management of cardiovascular risk in the peri-menopausal woman: a consensus statement of European cardiologists and gynaecologists. Eur Heart J 28: 2028-2040 [Abstract] [Full text]  
• Pignone, M., Earnshaw, S., Tice, J. A., Pletcher, M. J. (2006). Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis.. ANN INTERN MED 144: 326-336 [Abstract] [Full text]  
• Franco, O. H, Steyerberg, E. W, de Laet, C. (2006). The polypill: at what price would it become cost effective?. J. Epidemiol. Community Health 60: 213-217 [Abstract] [Full text]  
• Rothberg, M. B., Celestin, C., Fiore, L. D., Lawler, E., Cook, J. R. (2005). Warfarin plus Aspirin after Myocardial Infarction or the Acute Coronary Syndrome: Meta-Analysis with Estimates of Risk and Benefit. ANN INTERN MED 143: 241-250 [Abstract] [Full text]  
• Thompson, A., Temple, N. J (2004). The case for statins: has it really been made?. JRSM 97: 461-464 [Full text]  
• Campbell, N. C, Murchie, P. (2004). Treating hypertension with guidelines in general practice. BMJ 329: 523-524 [Full text]  
• Cooke, G A. (2004). Prevention of coronary heart disease: Is a cure too expensive?. BMJ 328: 405-405 [Full text]  
• Taylor, D., Jenkins, A., Conradi, P. (2004). Prevention of coronary heart disease: Statins are even less effective than paper shows. BMJ 328: 404-404 [Full text]  
• D'Avanzo, W. C (2004). Prevention of coronary heart disease: Incremental cost effectiveness raises issues. BMJ 328: 405-405 [Full text]  
• Messori, A., Santarlasci, B. (2004). Prevention of coronary heart disease: Data in table 2 could be shown more explicitly for better understanding. BMJ 328: 405-405 [Full text]  
• Warburton, R. N (2003). What do we gain from the sixth coronary heart disease drug?. BMJ 327: 1237-1238 [Full text]  

Rapid Responses:

Read all Rapid Responses

Coronary heart disease prevention

Undurti N Das, et al.
bmj.com, 29 Nov 2003 [Full text]

Coronary Heart Disease Prevention: Issues with Incremental Cost Effectiveness

William C D'Avanzo
bmj.com, 30 Nov 2003 [Full text]

Is a cure is too expensive?

G Alastair Cooke
bmj.com, 30 Nov 2003 [Full text]

Statins are even less effective

Philipp A. Conradi
bmj.com, 1 Dec 2003 [Full text]

Long-term efficacy of clopidogrel therapy

Jeffrey Mann
bmj.com, 3 Dec 2003 [Full text]

From the individual patient's perspective

Jeffrey Mann
bmj.com, 2 Dec 2003 [Full text]

Drugs and the Cause of Atheroma

Eddie Vos
bmj.com, 2 Dec 2003 [Full text]

simavastain costs falling

John N Fells
bmj.com, 2 Dec 2003 [Full text]

Further commentary on the long-term efficacy of clopidogrel in preventing adverse cardiac events

Jeffrey Mann
bmj.com, 4 Dec 2003 [Full text]

Statin side efffects

Michael O'Donnell
bmj.com, 4 Dec 2003 [Full text]

We should be looking at overall mortality

Malcolm E Kendrick
bmj.com, 4 Dec 2003 [Full text]

Simvastatin will be the "New Aspirin", even on Price

john s ashcroft
bmj.com, 5 Dec 2003 [Full text]

More thoughts on cost-effectiveness

Adam Jacobs
bmj.com, 5 Dec 2003 [Full text]

Tables of Marshall's article

Andrea Messori, et al.
bmj.com, 7 Dec 2003 [Full text]

More attention on the quality of the economic analyses is needed

Borislava N Mihaylova, et al.
bmj.com, 11 Dec 2003 [Full text]

Setting Risk Thresholds For Coronary Event Prevention

Tom Love, et al.
bmj.com, 15 Dec 2003 [Full text]

Author's response

Tom Marshall
bmj.com, 12 Dec 2003 [Full text]

Independence of treatment effects

Adam Jacobs
bmj.com, 13 Dec 2003 [Full text]

Online poll

Find out more>>