Results

Case study 38: Management of ischaemic heart disease

October 2005

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Inside
Case study 38: Management of ischaemic heart disease Scenario and questions Summary of results Results in detail Commentaries Associate Professor Ian Scott Dr David Gosling References page 11 page 13 page 15 page 3 page 4 page 6

The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence. Any treatment decision based on this information should be made in the context of the clinical circumstances of each patient.

Case study 38 Management of ischaemic heart disease

Scenario
John is a 64-year-old male new to the area who presents to the surgery. John reports that he has a history of hypertension (20 years) and angina (2 years). He was a heavy smoker, 30 per day for 48 years, but ceased 9 months ago. He has no history of gastrointestinal bleeding and nil known allergies. A letter from his previous GP reports that John had a non ST segment elevation myocardial infarction (NSTEMI) 12 months ago for which he under went a percutaneous transluminal coronary angioplasty and stent to his left coronary artery. John was involved in a cardiac rehabilitation program at the local hospital for six weeks after his discharge. Since then he walks briskly for 40 minutes every day and describes no angina. Current medications: aspirin 100 mg daily, clopidogrel (Iscover, Plavix) 75 mg daily, perindopril (Coversyl) 4 mg daily, simvastatin (Lipex, Simvar, Zocor) 20 mg daily. Further discussion identifies Johns lack of understanding of the purpose of his medicines and he admits to not always being compliant. On examination his blood pressure is 145/85 mmHg, pulse rate 80 per minute regular and his chest is clear on auscultation. Echocardiogram six months ago showed no evidence of heart failure. Body mass index is 23.5 kg/m2. Blood results taken six weeks ago were mostly normal but you note a total cholesterol of 5.5 mmol/L, low-density lipoprotein (LDL) cholesterol 3.9 mmol/L, high-density lipoprotein (HDL) cholesterol 0.8 mmol/L and triglycerides 1.8 mmol/L.

Questions for response

1. What changes (if any) would you make to Johns medication? Aspirin: cease continue cease continue increase dose: specify new dose ______ mg frequency ______ decrease dose: specify new dose ______ mg frequency ______ increase dose: specify new dose ______ mg frequency ______ decrease dose: specify new dose ______ mg frequency ______ If continuing clopidogrel, please indicate reason ______________ increase dose: specify new dose ______ mg frequency ______ decrease dose: specify new dose ______ mg frequency ______ increase dose: specify new dose ______ mg frequency ______ decrease dose: specify new dose ______ mg frequency ______ Dose Frequency

Clopidogrel:

Perindopril:

cease continue cease continue

Simvastatin:

2. List any drug(s) you would add to Johns regimen. Drug i. __________________________________________________________________________________ ii. __________________________________________________________________________________ iii. __________________________________________________________________________________ 3. Based on the new medication regimen, what do the medication(s) offer in cardiovascular risk reduction for John? ______________________________________________________________________________________ 4. List four points/strategies you would discuss/implement with John about his medicines to improve compliance. i. ___________________________________________________________________________________ ii. ___________________________________________________________________________________ iii. ____________________________________________________________________________________ iv. ____________________________________________________________________________________ 3

Summary of results
At the time of publication, 1118 responses had been received from doctors and other health professionals. Responses from 200 general practitioners have been compiled for feedback.

Changes to the current medication regimen

99% of respondents would continue aspirin; 97% would continue at the current dose. 75% would discontinue clopidogrel. 94% would continue perindopril; 45% would continue at the current dose and 50% would increase the dose (most commonly to 8 mg daily). 98% would continue simvastatin; 5% would continue with the current dose and 94% would increase the dose (most commonly to 40 mg daily).

Addition to the current medication regimen

48% would initiate a beta blocker, mostly atenolol or metoprolol. Other medications that were initiated included nitrates, diuretics and fish oil. 5% would initiate an ACE inhibitor/thiazide diuretic combination product, mostly perindopril/indapamide (in place of perindopril); 2% would initiate atorvastatin (in place of simvastatin).

Cardiovascular risk reduction offered by the new medication regimen

Respondents varied in their approach to this question; as intended, 29% described the relative risk reduction for cardiovascular morbidity and/or mortality offered by each medication in the regimen. Others described the benefits of the new medication regimen in terms of cardiovascular risk reduction in general (21%), improvement in blood pressure and/or lipid profile (37%) and prevention of the recurrence of ischaemic heart disease (15%).

Strategies to improve medication compliance

Patient education strategies included explaining the purpose, benefits and importance of the medications (63%), and explaining the importance of cardiovascular risk reduction and achieving tighter blood pressure and lipid control (36%). Strategies for regular follow-up and review included arranging regular appointments (49%) and monitoring treatment effects (49%). 53% suggested simplifying the medication regimen. Other strategies included psychosocial interventions (e.g. reaffirming patients efforts), compliance aids and obtaining external support (e.g. referring patients for Home Medicines Review).

Key points in management

Managing all existing cardiovascular risk factors is crucial in ischaemic heart disease and patients require multiple medications. Managing multiple risk factors concurrently can have additive effects in reducing the risk of myocardial infarction and death.1 Unless contra-indicated or not tolerated, low-dose aspirin remains the antiplatelet drug of first choice.2 A combination of clopidogrel and low-dose aspirin is recommended for up to 12 months after stent implantation, depending on the type of stent and circumstances of implantation.1 After that, maintenance therapy with low-dose aspirin alone is recommended.1,3 ACE inhibitor therapy should be considered in all patients, especially those at high risk (e.g. previous myocardial infarction, left ventricular dysfunction, heart failure, heart rate > 80 beats per minute, anterior infarct, diabetes mellitus, hypertension).1 Continue long term therapy in patients with left ventricular dysfunction or heart failure.2,4 Statin therapy should be started in all patients with ischaemic heart disease irrespective of pretreatment cholesterol levels.5 Treatment (accompanied by lifestyle changes) should aim to lower LDL-cholesterol to less than 2.5 mmol/L.1,2 Unless contra-indicated, beta blocker therapy should be started after myocardial infarction, and continued indefinitely.1,2,6 Atenolol, metoprolol and propranolol are approved for this indication.7 Effective interventions to improve patient compliance for chronic conditions usually involve multifaceted approaches8 (e.g. simplifying the medication regimen, organising follow-up appointments and providing information about medications).

Results in detail
Question 1. Changes to the current medication regimen
Table 1. Medication changes
Aspirin Continue without dose change (100 mg daily) Continue at increased dose (150 mg daily) Continue at decreased dose (75 mg daily) Discontinue* Clopidogrel Continue without dose change (75 mg daily) Discontinue

% of respondents (n = 200)
96.5 0.5 2.0 1.0 24.0 75.0 1.0 44.5 49.5 5.0 1.0 4.5 93.5 2.0

No response Perindopril Continue without dose change (4 mg daily) Continue at increased dose (most commonly 8 mg daily) Discontinue

No response Simvastatin Continue without dose change (20 mg daily) Continue at increased dose (most commonly 40 mg daily) Discontinue
* All respondents who discontinued aspirin continued with clopidogrel.

All respondents who discontinued clopidogrel continued with aspirin. Most respondents who discontinued perindopril started perindopril/indapamide combination product. All respondents who discontinued simvastatin started atorvastatin.

4% of respondents noted that any changes or additions made to the existing medication regimen will depend on an assessment of the patients compliance. Most respondents who continued clopidogrel did not provide a reason for doing so. For those who did, the main reasons for continuing clopidogrel included previous history of stenting and an assumption that John was using aspirin before the myocardial infarction. Other reasons included uncertainty of when to stop clopidogrel, no evidence of gastro-intestinal bleeding, and needing to seek clarification from the specialist who initiated clopidogrel.

Practice points
Unless contra-indicated or not tolerated, aspirin remains the antiplatelet drug of first choice in patients with ischaemic heart disease. Clopidogrel is at least as clinically effective and as safe but is not as cost effective as aspirin.2 A combination of clopidogrel and low-dose aspirin is recommended for up to 12 months after stent implantation, depending on the type of stent and circumstances of implantation.1 After that, maintenance therapy with low-dose aspirin alone is recommended.1,3 ACE inhibitor therapy should be considered in all patients, especially those at high risk (e.g. previous myocardial infarction, left ventricular dysfunction, heart failure, heart rate > 80 beats per minute, anterior infarct, diabetes mellitus, hypertension).1Dose increases should take into account not only the patients current blood pressure but also the potential hypotensive effects of other medications required by the patient (e.g. a beta blocker in this case). Statin therapy has been shown to prevent serious vascular events and death from any cause in patients with ischaemic heart disease.5 Treatment (accompanied by lifestyle changes) should aim to lower LDL-cholesterol to less than 2.5 mmol/L.1,2

Question 2. Addition to the current medication regimen

Table 2. Medication additions
Beta blocker Atenolol (most commonly 50 mg daily) Metoprolol (most commonly 50 mg daily or 25 mg twice daily) Carvedilol (titration pack) Unspecified Nitrate Isosorbide mononitrate (60 mg daily) Glyceryl trinitrate sublingual (when required) ACE inhibitor/angiotensin II receptor antagonist thiazide diuretic combination Perindopril/indapamide (4/1.25 mg daily) Candesartan/hydrochlorothiazide (16/12.5 mg daily) Diuretic Indapamide (1.5 mg daily) Hydrochlorothiazide (12.5 mg daily) Frusemide (20 mg daily) Fish oil HMG-CoA reductase inhibitor Atorvastatin (40 mg or 80 mg daily) Other (folic acid, vitamin B12, psyllium, amlodipine and ranitidine)
* Respondents may have more than one response.

% of respondents* (n = 200)
47.5 28.0 17.5 0.5 1.5 6.0 3.5 2.5 5.0 4.5 0.5 3.0 1.5 1.0 0.5 2.5 2.0 2.0 3.0

This replaced perindopril 4 mg daily. This replaced simvastatin 20 mg daily.

53% of respondents added one medication, 7% added two medications and 2% added three medications. A further 7% switched from an existing medication to another medication. 4% of respondents noted that any changes or additions made to the existing medication regimen depended on an assessment of the patients compliance.

Practice points
Unless contra-indicated, beta blockers should be started and continued indefinitely in all patients after myocardial infarction, as they significantly reduce morbidity and all-cause mortality.1,2,6 Atenolol, metoprolol and propranolol are approved for use in myocardial infarction (acute and longterm treatment).7 The usual long-term maintenance doses of beta blockers after myocardial infarction are:7 atenolol 50 mg daily metoprolol 50100 mg twice daily propranolol 80 mg twice daily.

Question 3. Cardiovascular risk reduction offered by the new medication regimen

Respondents varied in their approach to this question. As intended, 28.5% described the relative risk reduction for cardiovascular morbidity and/or mortality offered by each medication in the regimen (e.g. reducing blood pressure provides a 1525% relative risk reduction). Others described the benefits of the new medication regimen in terms of cardiovascular risk reduction in general (20.5%), improvement in blood pressure and/or lipid profile (36.5%) and prevention of the recurrence of ischaemic heart disease (14.5%).

Practice points
Managing multiple risk factors for ischaemic heart disease (e.g. elevated blood pressure and cholesterol levels, smoking, insufficient physical activity, obesity and diabetes9) can have additive effects in reducing the risk of myocardial infarction and death.1 Use of a beta blocker post myocardial infarction offers a 2030% relative risk reduction in cardiovascular morbidity and/or mortality from ischaemic heart disease.2 In Johns case, a beta blocker will confer additional benefits to those provided by his current lifestyle and drug treatments.

Question 4. Strategies to improve patient medication compliance

Table 3. Strategy
Patient education Explain purpose, benefits and/or importance of medications Explain and discuss importance of cardiovascular risk reduction (e.g. using cardiovascular risk calculator) and achieving tighter blood pressure and lipid control Emphasise importance of lifestyle interventions Provide verbal and/or written patient information and instructions Discuss importance of compliance and/or consequences of non-compliance Simplify medication regimen Regular follow-up and review Arrange regular appointments to review progress and/or compliance Monitor treatment effects (to demonstrate evidence of benefits) Use recall systems Contact patient if appointment missed Check compliance (e.g. monitor repeat prescriptions issued, count tablets) Establish care plans Psychosocial interventions Acknowledge and reaffirm patients efforts with smoking cessation and exercise Discuss patient concerns and compliance issues Discuss adverse effects of medications and address potential implications on compliance Assess for depression or mood changes Compliance aids Recommend dose administration aids (e.g. Dosette boxes, blister packs) Provide medication chart Support and assistance from external sources Consider referral for Home Medicines Review Involve family members Enlist help of other health professionals or support groups Other
* Respondents may have more than one response.

% of respondents* (n = 200)
63.0 36.0 15.0 14.5 8.0 52.5 48.5 33.0 8.0 6.5 4.0 1.5 11.0 10.5 10.5 3.5

11.0 2.5 6.0 5.5 3.5 12.5

Includes suggesting generic medications if cost is an issue, suggesting blood pressure monitoring at home and stressing that taking medications is the patients responsibility

Practice point
Effective interventions to improve patient compliance for chronic conditions usually involve multifaceted approaches.8 Single strategies do not help most patients, a combination of strategies such as those suggested in Table 3 may improve compliance long term.10

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Commentary 1
Key points In patients with known coronary artery disease it is imperative to aggressively treat all existing risk factors with an appropriate mix of pharmacological and non-pharmacological measures to achieve additive benefits in preventing early death and recurrent coronary events. Antiplatelet therapy and beta blockers should be used indefinitely. ACE inhibitor therapy is indicated long term in all patients with left ventricular dysfunction. In patients with preserved left ventricular function, such therapy is more controversial, with two trials suggesting modest reductions in cardiovascular events at 45 years follow-up, while a third showed no benefit. The benefits of intensive lipid lowering using high-dose statins have been confirmed in recent trials that achieved target levels of LDL-cholesterol of 1.6 mmol/L. Cardiac rehabilitation immediately after an event, followed by coaching programs that teach self-efficacy and compliance in secondary prevention, offer potential for reducing mortality over the medium term. John is a patient at high risk (5% per year) of further coronary events, given his previous NSTEMI and multiple risk factors of hypertension, long smoking history and hyperlipidaemia. While he appears, to his credit, to have adopted lifestyle modifications such as abstinence from smoking and regular exercise, he is not always compliant with medications, and his blood pressure and lipid levels remain less than optimally controlled. In his favour, he is not overweight and has preserved left ventricular systolic function, according to recent echocardiography. Antiplatelet therapy Unless contra-indicated, low-dose aspirin should be continued indefinitely, as agreed by virtually all respondents. However, one-quarter were also keen to continue clopidogrel, which I would prescribe for up to 12 months after coronary 11

Associate Professor Ian Scott Director, Department of Internal Medicine Princess Alexandra Hospital Brisbane QLD

artery stenting, or long term in patients who suffer recurrent acute coronary syndromes with ST-segment deviation or elevated troponin level. Otherwise, in the absence of ongoing ischaemia, the combination of clopidogrel and aspirin has not been shown to confer additional benefit over aspirin alone, is expensive and increases the risk of major bleeding, including gastro-intestinal haemorrhage. ACE inhibition Most respondents wanted to continue perindopril (94%), with half of these opting for an increase in dose. Results of the HOPE11 and EUROPA12 trials suggest that all patients with coronary artery disease, even if clinically stable with normal ventricular function and at lower risk, benefit from use of ACE inhibitor over a 45 year period. Between 25 and 50 patients need to be treated to prevent one cardiovascular event. In contrast, in the PEACE trial,13 in which most patients had undergone coronary revascularisation and were receiving lipidlowering agents, as is the case with John, there was no additional reduction in cardiovascular events with the ACE inhibitor trandolapril, compared with placebo. Despite these discordant trial results, one could argue that John deserves an ACE inhibitor, in light of his elevated cholesterol levels (see below) and his current blood pressure readings of 145/85 mmHg (compared with target values of 130/80 mmHg) particularly as a mean blood pressure of 133/78 mmHg was noted in patients in the PEACE trial. Lipid management Most respondents would continue simvastatin and more than 90% would increase the dose. Recent trials of intensive lipid reduction in patients with stable coronary disease or after acute coronary syndrome show that achieving LDL-cholesterol levels as low as 1.6 mmol/L, compared with the usual target of 2.5 mmol/L, results in a 1622% reduction in cardiovascular events over 25 years, with the number needed to treat ranging between 25 and 50.14, 15 Both trials used high-dose atorvastatin (80 mg/day) as

the intensive reduction strategy, although trials have yet to confirm whether a lower dose of atorvastatin (40 mg/day), or use of other statins at higher than conventional dosages, may be as effective with less risk of statin-induced toxicity. In Johns case, his current LDL-cholesterol value of 3.9 mmol/L is clearly too high, and increasing his dose of simvastatin is indicated. Blood pressure control ACE inhibitors and beta blockers are useful in treating hypertension in patients with coronary disease, given their combined antihypertensive and cardioprotective effects. If patients prove intolerant of ACE inhibitors, angiotensin II receptor antagonists are alternative agents. Combination therapy with low-dose thiazides is effective therapy in cases of more resistant hypertension. Beta blocker cardioprotection Evidence clearly shows that beta blockers reduce all-cause and coronary mortality in unselected patients after myocardial infarction, at least for up to 2 years.6 While no analysis has compared the effects of beta blockers in patients who have undergone post-infarct coronary revascularisation with those who have not, it is still likely that beta blockers confer benefit because of the risk of disease progression in native arteries or subsequent occlusion of grafts or stents. Less than half of respondents chose to initiate beta blocker therapy, which may reflect a perception that, in the absence of exertional angina, systolic dysfunction or elevated blood

pressure, these drugs do not confer added benefit this is contrary to current evidence. Role of nitrates Most respondents chose not to prescribe nitrates, which is in keeping with the paucity of evidence for routinely administered oral or transcutaneous nitrates to prevent coronary events or lower mortality in patients without symptoms of angina or silent myocardial ischaemia. This is in contrast to the acute management of myocardial infarction, in which intravenous nitrates limit infarct size and reduce short-term mortality.16 Lifestyle modification Cardiac rehabilitation17 and coaching programs18 (direct one-on-one counselling with strong emphasis on disease self-management) reduce long-term mortality and morbidity. These programs are multifaceted and multidisciplinary and focus on patient education, exercise training, weight reduction, dietary change, medication compliance, psychological assessment, and home and community support. While two-thirds of respondents regarded patient education as important, less than half suggested regular review and monitoring of management goals, and only 11% thought psychosocial interventions were worthwhile. However, evidence supports an approach that integrates all these elements and that is sustained over the long term with repeated follow-up.

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Commentary 2
Overview The scenario presented in the case study would be familiar to general practitioners on a weekly, if not daily, basis. The management of ischaemic heart disease is a basic part of general practice. The case study is well designed to illustrate the potential difficulties in: managing patients post myocardial infarction preventing secondary cardiac events establishing rapport with a complex new patient. The management of ischaemic heart disease is a constantly changing area of medicine and therefore a challenge for the busy GP to keep up with. The evolving themes in both management of post-myocardial infarction and secondary prevention have been towards ever more aggressive attention to risk factors, lifestyle modifications and drug interventions, as evidence of cost effectiveness for such initiatives continues to arrive from clinical trials. Good clinical evidence exists for routine use of certain drug interventions post myocardial infarction, including ACE inhibitors, low-dose aspirin, beta blockers and statins. ACE inhibitors are used both for preventing progression to cardiac failure after myocardial infarction19 and reducing the incidence of subsequent cardiac events20, with very early initiation (first 24 hours) now the accepted norm. The use of beta blockers after myocardial infarction has been established for more than 20 years.21 It has long been known that lipid levels measured at the time of myocardial infarction do not necessarily reflect the usual levels for the patient, and data from trials of aggressive lipid lowering regardless of pre-infarction levels22 suggest all patients at high cardiovascular risk (including post myocardial infarction) tolerant of statins should start on the equivalent of at least 40 mg/day simvastatin.5

Dr David Gosling General Practitioner Taree, NSW

Use of clopidogrel and aspirin for the first 12 months after stent placement has been established.23 Desirable parameters for lipid levels, blood pressure, weight and exercise have been established and it is apparent that John is falling short in several areas. As he is a new patient, John must reach an understanding of the treating doctors aims, and the doctor must reach an understanding of the various factors affecting Johns ability to help meet those aims. It is apparent that John is not using a beta blocker. He is still over target with his blood pressure, and his lipid profile indicates that total cholesterol is too high at 5.5 mmol/L and HDL too low at 0.8 mmol/L. He lacks understanding of the purpose of his medications and his compliance is imperfect. The biggest impediment to success in managing risk factors is a lack of understanding and motivation on the patients part. Time will have to be spent educating this new patient so that he clearly understands the key concept of treatment to target or to maximally tolerated doses of medications. Comments on the summary of results Pleasingly, most respondents indicated that they would increase the dosage of simvastatin to 40 mg/day. Respondents were less certain about the need to increase the perindopril dose to 8 mg as the first step towards better control of blood pressure as well as reducing the probability of vascular events. Fewer than half would add a beta blocker. In the absence of ongoing angina there is little evidence to support the use of nitrates; moreover, in such cases the addition of nitrates is not likely to be tolerated because of side effects. There are no good data indicating that continuing clopidogrel beyond 12 months is of benefit, and it should be discontinued after explanation to the patient. Reluctance on the part of some GPs to discontinue medications

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started by specialists commonly leads to perpetuation of drug treatment only intended for the short term. If uncertain, the treating GP should contact the specialist to clarify such issues. More than half the respondents suggested simplifying the medication regimen; however, apart from switching from simvastatin to atorvastatin (morning dose) and discontinuing clopidogrel, there is no scope for reducing medication. The main emphasis should be on

educating the patient on the importance of the total package of preventive strategies, including the rather demanding number of tablets to be taken. It is worthwhile checking what, if any, over-the-counter medications the patient is taking, as NSAIDs in particular could interfere with prescribed medications. More regular appointments could help with patient education and rapport building, but fewer than half of the respondents suggested this.

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References
1. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand. Reducing risk in heart disease 2004: guidelines for preventing cardiovascular events in people with coronary heart disease. National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand, 2004. http://www.heartfoundation.com.au/downloads/RRIHD_fullguide_update_010405.pdf (accessed 22 August). New Zealand Guidelines Group. The assessment and management of cardiovascular risk. Wellington: New Zealand Guidelines Group, 2003. http://www.nzgg.org.nz/guidelines/0035/CVD_Risk_Full.pdf (accessed 5 September). National Institute for Clinical Excellence. Technology Appraisal Guidance 80: Clopidogrel in the treatment of non-ST-segment elevation acute coronary syndrome. London: National Institute for Clinical Excellence, 2004. http://www.nice.org.uk/pdf/TA080fullguidance.pdf (accessed 5 September). Writing Group for Therapeutic Guidelines: Cardiovascular. Therapeutic Guidelines: Cardiovascular. Version 4. Melbourne: Therapeutic Guidelines Ltd, 2003. Heart Protection Study Collaborative Group. 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. Freemantle N, Cleland J, Young P, et al. Beta-blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730-7. Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2005. Haynes RB, McDonald HP, Garg AX. Helping patients follow prescribed treatment. JAMA 2002;288:2880-3. Australian Institute of Health and Welfare. Heart, Stroke and Vascular diseases Australian facts 2004 (AIHW Cat. No. CVD 27). Cardiovascular Disease Series No.22. Canberra: Australian Institute of Health and Welfare and National Heart Foundation of Australia, 2004. http://www.aihw.gov.au/publications/cvd/hsvd04.pdf (accessed 6 September).

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10. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions. JAMA 2002;288:2868-79. 11. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145-53. 12. The European trial on reduction of cardiac events with perindopril in stable coronary artery disease investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782-8. 13. Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-68. 14. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary artery disease. N Engl J Med 2005;352:1425-35. 15. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

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16. Yusuf S, Collins R, MacMahon S, et al. Effect of intravenous nitrates on mortality in acute myocardial infarction: an overview of the randomised trials. Lancet 1988;331:1088-92. 17. Jolliffe JA, Rees K, Taylor RS, et al. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev 2001;(1). Art. No: CD001800. 18. Vale MJ, Jelinek MV, Best JD, et al. Coaching patients with coronary heart disease to achieve the target cholesterol: a method to bridge the gap between evidence-based medicine and the "real world" randomized controlled trial. J Clin Epidemiol 2002;55:245-52. 19. Pfeffer M, Braunwald E, Moye L, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992;327:669-77. 20. Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-84. 21. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71. 22 Sacks F, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.

23. Steinhubl SR, Berger PB, Tift Mann J, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomised controlled trial. JAMA 2002;288: 2411-21.

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