Case study 67 report: CVD risk: guiding lipid management

May 2011

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Inside
Case study 67: CVD risk: guiding lipid management Scenario and questions Summary of results Results in detail Assessing absolute cardiovascular risk Lifestyle interventions to reduce cardiovascular risk Lipid-modifying therapy with a statin Monitoring parameters after initiation of a statin Place of ezetimibe in lipid management Long-term adherence to lipid-modifying therapy page 6 page 7 page 8 page 9 page 10 page 11 page 3 page 5

Commentaries Professor Mark Nelson Dr David Peiris References page 12 page 13 page 15

This information is derived from a critical analysis of a wide range of authoritative evidence. NPS has taken reasonable care to ensure that the information is accurate and up to date at the time of creation. NPS does not warrant its completeness and excludes liability where permitted by law. Health care professionals must continue to rely on their own skill, care and enquiries, taking into account the individual circumstances of each patient when providing medical advice. Copyright: 2011 National Prescribing Service Limited. This work is copyright. You may download, display print and reproduce this work in unaltered form only (retaining this notice) for non-commercial use either personally or within your organisation. Apart from any such use or otherwise as permitted under the Copyright Act 1968, all rights are reserved. Queries concerning reproduction and rights should be sent to copyright@nps.org.au.

Case study 67 CVD risk: guiding lipid management

Scenario
Ric is a 49-year-old IT consultant who has come to see you concerned that he is at risk of a heart attack. Ric has type 2 diabetes, diagnosed 2 years ago, which is well controlled. He has a family history of type 2 diabetes and his father died recently of a heart attack at age 73. There is no other significant family history. Ric has 6 or 7 alcoholic drinks per week and smokes 10 cigarettes a day (he has tried to quit a number of times without success). Rics only exercise is his weekly social game of squash, and his lunch often consists of take-away meals. Ric takes controlled-release metformin 1000 mg in the evening. On-examination his waist circumference is 100 cm, blood pressure 130/82 mmHg, resting pulse 75 beats per minute with regular rhythm. Rics total cholesterol is 6.1 mmol/L, HDL-cholesterol 1.6 mmol/L, LDLcholesterol 3.85 mmol/L and triglycerides 1.4 mmol/L. Renal function, liver function tests, full blood count, glucose levels and HBA1c are all within normal range.

1. a) What is Rics calculated absolute cardiovascular risk over the next 5 years? low (<10%) moderate (10% to 15%) high (>15%)

b) Which cardiovascular risk tool/calculator did you use to calculate your answer? c) Are there any additional risk factors not considered by this cardiovascular tool that you would include in Rics formal CV risk assessment? (Please list) ______________________________________________________________________________________ 2. List three lifestyle interventions (in order of importance) that you would recommend to assist Ric in reducing his cardiovascular risk. _______________________________________________________________________________________ _______________________________________________________________________________________ _______________________________________________________________________________________ 3. a) Would you consider statin therapy appropriate for Ric? Please provide a reason for your answer. yes (give details) no Statin: ____________________________ Dose: __________________ Frequency: _________________ Reason: ______________________________________________________________________________ b) List three clinical parameters that you would monitor if starting Ric on a statin: _____________________________________________________________________________________ _____________________________________________________________________________________

4. a) When would you consider ezetimibe appropriate in managing Rics lipid profile? (mark all that apply) as first-line therapy in combination with a statin on initiation if a statin is not tolerated if all statins are not tolerated when a statin is not adequate alone (in combination) never other (specify) _____________________________________________________________________

5. How would you encourage Ric to adhere to lipid-modifying therapy long term? _______________________________________________________________________________________ _______________________________________________________________________________________ _______________________________________________________________________________________

Summary of results
At the time of publication, 1383 responses had been received from all participants, and 200 of those received from doctors have been compiled for feedback.

Case synopsis
Ric, a 49-year-old IT consultant, is concerned he is at risk of a heart attack. He has type 2 diabetes well controlled on metformin 1000 mg once a day. He has a family history of type 2 diabetes and his father died recently of a heart attack at age 73. On examination his waist circumference is 100 cm and his serum lipids are elevated. Ric smokes and has 6 or 7 alcoholic drinks a week. His lunch often consists of take away food and his only exercise is a social game of squash once a week. (See page 3 for more details.)

Assessing absolute cardiovascular risk

Seventy per cent of respondents correctly calculated Rics absolute cardiovascular risk as moderate (10% to 15%). To calculate Rics absolute cardiovascular risk, 58% of respondents used the Australian cardiovascular risk charts. Additional risk factors that respondents would include in their comprehensive cardiovascular risk assessment included Rics body weight (29%), family history (24%) and level of physical activity (20%).

Lifestyle interventions to reduce cardiovascular risk

A number of lifestyle interventions were listed by respondents to recommend to Ric, including: smoking cessation (32%) regular physical activity (29%) decreasing dietary fat intake (25%).

Lipid-modifying therapy with a statin

Ninety-two per cent of respondents considered a statin as appropriate therapy for Ric. These included atorvastatin (59%), rosuvastatin (29%) and simvastatin (10%).

Monitoring parameters after initiation of a statin

Serum lipid levels (37%), liver functions tests (25%) and creatine kinase (18%) were suggested clinical parameters requiring monitoring after starting Ric on a statin.

Place of ezetimibe in lipid management

Ezetimibe was considered appropriate when a statin is not adequate alone (40%) or if Ric was not able to tolerate all statins (33%). Fewer than 1% of respondents considered ezetimibe first-line therapy in lipid management.

Long-term adherence to lipid-modifying therapy

Strategies to encourage Ric to adhere to lipid-modifying therapy in the long term included: counselling (23%) regular review (21%) provision of education to Ric about his cardiovascular health (19%).

Results in detail
Assessing absolute cardiovascular risk
Respondents were asked to calculate Rics absolute cardiovascular risk over the next 5 years. Seventy per cent of respondents correctly calculated Rics risk as moderate (10% to 15%).Respondents were asked to specify which cardiovascular tool/calculator used to calculate Rics absolute cardiovascular risk (Table 1). Additional risk factors (not included in the cardiovascular tool/calculator) that respondents would take into account when conducting a comprehensive cardiovascular risk assessment are presented in Table 2.

Table 1: Tools used to calculate absolute cardiovascular risk

Tool
Australian cardiovascular risk charts New Zealand cardiovascular risk charts Clinical assessment NVDPA* Australian absolute CVD risk calculator Framingham risk equation Medical Director prescribing software No tool used
* National Vascular Disease Prevention Alliance

% of respondents (n = 198)*
58 26 7 4 3 1 1

Table 2: Additional CVD risk factors included in a comprehensive CV risk assessment

Risk factors
Body weight Family history Level of physical activity Diet Alcohol intake Presence and control of existing diabetes Serum lipid levels Current cardiovascular health Ethnicity Other

% of respondents (n = 200)*
29 24 20 6 6 5 3 3 2 2

* Respondents may have more than one response Serum lipid levels included LDL cholesterol (< 3%) and triglycerides (< 0.5%) Current cardiovascular health included left ventricular hypertrophy (1%), ECG (<1%), previous myocardial infarction (<0.5%) and existing vascular disease (< 0.5%) Other included mental health (< 1%), motivation to make health lifestyle changes (<1%), liver function (< 0.5%) and unspecified (< 0.5%)

Practice points
Assess absolute cardiovascular risk for all adults aged 4574 years ( 35 years for Aboriginal and Torres Strait Islander peoples), except those known to be at high risk. High absolute cardiovascular risk can be assumed for adults with1: systolic blood pressure 180 mmHg or diastolic blood pressure 110 mmHg moderate or severe chronic kidney disease familial hypercholesterolaemia diabetes and age > 60 years or with microalbuminuria serum total cholesterol > 7.5 mmol/L cardiovascular disease. Use a validated cardiovascular risk calculator to estimate absolute cardiovascular risk.2 Australian guidelines recommend the Australian cardiovascular risk charts or associated web calculator1 (see www.nps.org.au/cvdrisktools). Conduct a comprehensive cardiovascular risk assessment that includes risk factors not accounted for in the calculator.1 Other risk factors include: waist circumference and body mass index nutrition physical activity level alcohol intake family history of premature cardiovascular disease social history (cultural identity, ethnicity, socioeconomic status) mental health familial hypercholesterolaemia evidence of atrial fibrillation kidney function.

Lifestyle interventions to reduce cardiovascular risk

Respondents were asked to identify lifestyle interventions for Ric to assist in reducing his cardiovascular risk. Table 3 summarises the lifestyle interventions that respondents would recommend.

Table 3: Recommended lifestyle interventions for Ric

Lifestyle interventions
Smoking cessation Regular physical activity Decreasing dietary fat intake Decreasing body weight Decreasing alcohol intake
* Respondents may have more than one response

% of respondents (n = 200)*
32 29 25 10 4

Practice points
Encourage lifestyle changes in all patients, as changes can reduce absolute cardiovascular risk with or without pharmacological interventions over and above lowering serum lipid levels.3 Assist patients to undertake lifestyle changes by informing them that a moderate reduction of several risk factors can be more effective in reducing absolute risk than a major reduction in one.4

Provide comprehensive information to the patient about the five lifestyle risk factors that are responsible for at least 60% of coronary heart disease events:5 smoking BMI > 30 kg/m2 little or no physical activity poor diet alcohol.

Prioritise smoking-cessation strategies, as smokers have a 70% greater risk of death from coronary heart disease than non-smokers.4 This excess risk is reduced by 50% one year after cessation and declines gradually thereafter.6 Tailor lifestyle advice to individual patients needs, set realistic goals and give regular encouragement. Respond positively to any incremental success, even if targets have not been achieved.

Lipid-modifying therapy with a statin

Ninety-two per cent of respondents would consider statin therapy appropriate for Ric. Of the respondents who considered statin therapy appropriate, 59% indicated they would start atorvastatin. Table 4 summarises statin therapy for Ric as suggested by the respondents. Reasons why respondents consider statin therapy appropriate for Ric are summarised in Table 5. Of those respondents who did not consider statin therapy appropriate for Ric (8%), most reasoned that they would address lifestyle factors first.

Table 4: Statin therapy for Ric

Statin
Atorvastatin Rosuvastatin Simvastatin Fluvastatin Pravastatin Other

% of respondents (n = 180)
59 29 10 < 1% < 1% < 1%

Of the respondents who would start atorvastatin, 43% would initiate at 20 mg and 31% would initiate at 40 mg. Of the respondents who would start rousovastatin, 62% would initiate at 10 mg. Of the respondents who would start simvastatin, 61% would initiate at 40 mg.

Table 5: Reasons why statin therapy is considered appropriate for Ric

Reason
Rics raised serum lipid results Rics cardiovascular risk level Presence of diabetes diagnosis Rics medical family history Efficacy of statin therapy Other Rics smoking status Favourable adverse-effect profile of statins

% of respondents (n = 184)*
30 25 22 7 5 5 4 2

* Respondents may have more than one response Other included: meets PBS criteria (2%), Rics age (2%), taken in conjunction with lifestyle changes (0.5%), and statin use is dependent on current serum lipid-level results (0.5%)

Practice points
Prescribe lipid-modifying drug treatment for people with cardiovascular disease, a known high-risk condition, a high cardiovascular risk score or moderate cardiovascular risk score plus metabolic syndrome or a family history of early coronary disease3: clinical trials have shown the benefit of a statin is greatest for those at greatest risk of a cardiovascular event.7,8 Statins differ in LDL-lowering efficacy9, but there is no evidence to suggest one statin is more effective in reducing cardiovascular events than all the others: evidence suggests that the efficacy of statins in reducing cardiovascular risk depends on the extent of LDLcholesterol lowering rather than the specific drug used.10 Consider starting patients on a dose that has been shown to lower LDLcholesterol by 30% to 40%; contemplate higher doses for patients with recent myocardial infarction or acute coronary syndrome.11 Doses should be individualised to maximise patient adherence: most placebo-controlled clinical trials for primary prevention have used doses that lower LDLcholesterol by 30% to 40%; these regimens reduced the relative risk of cardiovascular events by about 30% and were generally well tolerated.8,12 more than 80% of the lipid-lowering effect of a statin is achieved at 50% of maximum dose.13 initiate statins at a low dose and increase as necessary;13 major adverse effects of statins tend to be dose-related.14

Monitoring parameters after initiation of a statin

Respondents were asked to list clinical parameters that they would monitor if starting Ric on a statin. Thirty-seven per cent would monitor serum lipid levels. The clinical parameters that respondents would monitor are summarised in Table 6.

Table 6: Clinical parameters to monitor when starting Ric on a statin

Clinical parameters
Serum lipids Liver function tests Creatine kinase Adverse effects Lifestyle changes (including weight loss) Kidney function Medicine compliance Other

% of respondents (n = 200)*
37 25 18 12 4 2 1 1

* Respondents may have more than one response Serum lipids included LDL cholesterol (11%), unspecified serum lipids (11%), total cholesterol (10%), HDL cholesterol (3%) and triglycerides (2%) Adverse effects included muscle pain (10%) and unspecified adverse effects (2%) Other included HBA1C (0.5%) and ECG (0.5%)

Practice points
Measure creatine kinase at baseline and thereafter only when clinically indicated (e.g. if muscle symptoms occur).13 Measure baseline liver enzymes before inititating a stain13 and at 12 weeks after initiation therapy, after a dosage change and if signs of symptoms related to hepatotoxicity occur.15,16

Place of ezetimibe in lipid management

Respondents were asked to indicate when they considered ezetimibe appropriate in managing Rics lipid profile. Ezetimibe was considered by respondents, to be appropriate for Ric when a statin alone was not adequate (40%) or when all statins were not tolerated (33%). Table 7 summarises the results.

Table 7: Appropriate place of ezetimibe in Rics lipid management

Role of ezetimibe
When a statin is not adequate alone (in combination) When all statins are not tolerated When a statin is not tolerated Combined with a statin on initiation Other

% of respondents (n = 200)*
41 32 23 2 2

* Respondents may have more than one response Other included: first-line therapy (0.5%), presence of mixed hyperlipidaemia (0.5%),high statin dose ineffective or not tolerated (0.5%), familial hypercholesterolaemia (< 0.5%), risk of future cardiovascular event (< 0.5%), and never (< 0.5%)

Practice points
Ensure patients have received adequate period of statin therapy together with lifestyle changes (> 3 months), before considering ezetimibe.17 Limit ezetimibe for people who cannot tolerate a statin, or as adjuvant therapy for people who require but cannot tolerate a high statin dose10: differences in the LDL-lowering effect of ezetimibe and statins (18% and 30% to 50%, respectively) should be considered when selecting appropriate lipid-management therapies. When used in combination ezetimibe increases the LDL-lowering effect of a statin (by up to 20%).13 there is limited data to suggest that 10 mg/day of ezetimibe (as monotherapy or as adjunctive therapy to a statin) reduces cardiovascular disease morbidity and mortality.

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Long-term adherence to lipid-modifying therapy

Respondents were asked how they would encourage Ric to adhere to his lipid-modifying therapy in the long term. Counselling (23%) and regular review (21%) were most commonly suggested. Table 8 summarises the results.

Table 8: Strategies to encourage Rics adherence to lipid-modifying therapy

Strategies
Counselling (including motivation interviewing) Regular review Provide education to Ric regarding his cardiovascular health Use a tool to reinforce cardiovascular risk Involve the patient in management decisions Regular reminders Discuss adherence Referral to support programs Other
* Respondents may have more than one response Tool refers to unspecified cardiovascular risk assessment tool, i.e. risk calculator or risk charts Other included specific dosage instructions (< 2%) and unspecified (< 0.5%)

% of respondents (n = 200)*
23 22 19 14 6 5 5 4 2

Practice points
Identify and address factors that can influence a patients adherence to medication:18 lack of knowledge denial adverse effects poor memory adverse attitude to treatment. Reinforce the benefits of statin therapy to the patient at every opportunity. Simple reminders are one of the most effective ways of encouraging adherence.18

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Commentary 1
Key points
Dyslipidaemia should be managed in the setting of absolute cardiovascular disease risk. Absolute cardiovascular disease risk needs to be estimated with an absolute risk calculator. Statin use is determined by PBS criteria but high-risk individuals who dont qualify can be prescribed generically. Behavioural change remains the basis for cholesterol lowering. If treating dyslipidaemia with drugs, manage to treatment goals. Lipid disorders are a common problem managed in general practice.19 They should not be managed in isolation. When to intervene is best established by estimating absolute cardiovascular disease risk, which takes all major risk factors into account.20 Behavioural modification remains the basis of management with drug therapy recommended to those with residual high absolute risk. A large body of evidence supports the use of lipid-modifying therapy for reducing the risk of cardiovascular disease, primarily via reducing LDLcholesterol (LDL-c) level, with the most convincing data for statins.20 These agents should generally be used first line for cardiovascular protection. Once the decision has been made to treat, dyslipidaemia should be treated to National Heart Foundation treatment goals to avoid leaving the patient at residual risk. his age

Prof Mark Nelson Chair of General Practice, and Senior Member Menzies Research Institute University of Tasmania

Factors exacerbating and contributing to Rics dylipidaemia include: visceral obesity, as witnessed by abdominal circumference being sedentary diet family history. Smoking does not increase cholesterol per se but is the most important modifiable risk factor for cardiovascular disease and should be preeminent in recommended behavioural change. It was the most common lifestyle intervention proffered (32%) but should be universal.

Use of statins
Ric qualifies for a statin under the PBS, and their use is reasonable given his additional risk factors of visceral obesity, sedentary lifestyle, and paternal history of a cardiovascular disease (died at 73 but no information on age of onset, by which additional risk is established). However, delayed use with lifestyle, as selected by 59% of respondents, is also reasonable given his calculated intermediate risk.

Monitoring after initiation of a statin

Monitor lipids and fractions 46 weekly until treatment goals are reached. Pre-treatment LFTs are recommended, with re-assessment in the presence of side effects (LFTs, creatine kinase if myalgia is present).2 It is important to check adherence to therapy if targets are not being met, before dose adjustments.

Case scenario
Rics absolute risk calculated on the Australian absolute cardiovascular disease risk calculator (found at www.cvdcheck.org.au) is 12%. Ninety-one per cent of respondents used an absolute risk calculator, which is a historically high rate in Australian general practice. Although this is likely to be an overestimation due to responder bias for NPS case studies, it is a positive finding. However. not all came up with the correct risk category of 10-15% (70%).

Take-home messages
Dyslipidaemia should be managed holistically with other cardiovascular disease risk factors through calculation of absolute cardiovascular risk. Lifestyle change (particularly smoking cessation) is the basis of management. Immediate drug therapy is warranted in high-risk individuals. Dyslipidaemia (and other risk factors) should be managed to treatment goals to avoid leaving the patient at adverse residual risk.

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Commentary 2
Key points
Management decisions should be guided by a patients overall or absolute risk, using tools based on the Framingham Risk Equation and assessment for other common risk factors not included in this equation. Intensive lifestyle advice is recommended for patients at moderate risk of CVD events and pharmacological treatment with both bloodpressure- and lipid-lowering medication should be considered when appropriate. Strategies that actively engage patients in lifestyle changes and medication adherence should be instituted.

Dr David Peiris Senior Research Fellow and General Practitioner The George Institute for Global Health University of Sydney

It is validated for people aged 3074 years without established cardiovascular disease. The Australian and New Zealand risk prediction colour charts are based on this equation, and most respondents used these charts to correctly estimate Rics risk as being in the 1014% range. There is also an online calculator version of the FRE (www.cvdcheck.org.au) and some practice software systems and third-party tools such as the recently launched PrimaryCare Sidebar have an FRE calculator built in. Although Rics calculated risk is moderate, his case highlights the importance of identifying other risk factors not included in the FRE. Their presence suggests that risk may be underestimated by the FRE alone, and this may change management decisions. Some important and easy-to-measure risk factors include: a family history of premature cardiovascular disease elevated body mass index markers of chronic kidney disease socioeconomic hardship depression. In Rics case it is particularly important to assess for chronic kidney disease due to his diabetes. Proteinuria, albuminuria and reduced glomerular filtration rate are each independently and strongly associated with cardiovascular disease events. Although Rics renal function was reported as normal, the presence of albuminuria would result in his risk being reclassified from moderate to clinically high risk based on National Vascular Disease Prevention Alliance recommendations.1 Although many respondents identified body mass index and family history as being important, no respondents considered albuminuria screening to be part of a comprehensive CVD risk assessment. Assuming Ric does not have albuminuria, intensive lifestyle management and consideration of pharmacological management of his blood pressure and lipids is appropriate.

Comments
Rics presentation represents a key opportunity to comprehensively assess his risk of a cardiovascular disease event. Estimating his risk requires simultaneous assessment of several risk factors. There has been a fundamental shift away from screening and managing single riskfactor abnormalities (e.g. hypertension or hypercholesterolaemia) toward a global assessment of multiple risk factors. This absolute risk approach provides greater ability to predict who is at greatest risk of a cardiovascular disease event than the traditional management of single risk factors.21 A number of absolute cardiovascular disease risk-prediction equations have been developed based on cohort studies. One of the most commonly used is the Framingham Risk Equation (FRE). To determine a persons risk of a cardiovascular disease event (commonly calculated over 5 years1) the FRE uses: age sex diabetes status systolic blood pressure smoking status blood pressure total and HDL cholesterol the presence of left ventricular hypertrophy.

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Surprisingly, only a minority of respondents identified smoking cessation as a key lifestyle intervention. Intensive psychological and pharmacological support for smoking cessation should be offered to Ric, particularly given his past quit attempts and current concerns about heart disease. Australian physical activity and dietary guidelines recommend: at least 30 min/day of moderate activity (enough to get short of breath) on most days of the week reduction in saturated fats decreased overall caloric intake for those with excess body weight. Salt reduction to <4g/day and alcohol reduction can also make a substantial contribution to lowering blood pressure.22 There is good evidence that BP lowering, even at Rics current level of 130/82mmHg, can reduce all-cause mortality and risk of cardiovascular disease events.23 Intensive management of Rics lifestyle risks could lower his systolic BP by about 24 mmHg and therefore assist in reducing his overall cardiovascular disease risk. If this cannot be achieved via intensive lifestyle measures, consideration should be given to offering him BP-lowering medication. An ACE inhibitor is recommended first-line treatment for people with diabetes.22 The role of aspirin in primary prevention for people with diabetes is a current controversy, with recent meta-analyses suggesting an unfavourable riskbenefit ratio. Further trials are ongoing to more definitively answer this question. The vast majority of respondents considered lipid management with a statin to be appropriate for Ric due to his elevated LDL-c levels, moderate risk and presence of diabetes. This is consistent with current guidelines24 and trial outcomes for people with diabetes.25 Ric qualifies for statin subsidy under the PBS. The key goal of lipid management is to lower his LDL-c. There is evidence from secondary and primary prevention trials to suggest intensive LDL-c reduction reduces cardiovascular disease events.26 While rosuvastatin and atorvastatin are the most potent agents within this class, there is no evidence to demonstrate the superiority of one

agent over another in the context of similar LDL lowering.27 Whatever the statin chosen, most respondents appropriately initiated treatment at moderate-strength doses. Statins are generally very well tolerated and have a good safety profile.7 Many respondents highlighted the need for creatine kinase and liver function monitoring when starting Ric on a statin. The risk of rhabdomyolysis is very small (<1/100,000).24 Current Australian guidelines recommend measuring serum creatine kinase before starting treatment. Further measurement is not indicated unless the patient becomes symptomatic. A higher index of suspicion is recommended if the patient is on concomitant fibrate treatment, antifungals or other cytochrome p450 inhibitors. Caution is also advised for the elderly and those with chronic kidney disease. There is a low incidence of elevated liver enzyme levels (00.8%) with statins and these are usually dose dependent and reversible on cessation.24 Although ezetimibe has emerged as a useful adjunct for LDL-c lowering in combination with statins28, there are still limited data on its ability to reduce cardiovascular disease events or allcause mortality. It is currently indicated in Australia for use only as second-line therapy in combination with statins or when statins are contraindicated, which is consistent with respondents answers in Rics case. Respondents all highlighted the need for ongoing review and support for Ric to assist with adherence. Low medication adherence rates are a well-documented, highly prevalent barrier to translating evidence into practice. The reasons for non-adherence are complex but are known to include29: complex dosing regimens with multiple pills inadequate knowledge about the medicines cost. Factors associated with improved adherence include30,31: dose-administration aids home medicine reviews reduced dosing demands regular feedback and monitoring.

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References
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24. National Heart Foundation of Australia, Cardiac Society of Australia and New Zealand. Position statement on lipid management 2005. Heart Lung Circ 2005;14:27591. 25. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebocontrolled trial. Lancet 2003;361:200516. 26. Cholesterol Treatment Trialists C. Efficacy and safety of more intensive lowering of LDL cholesterol: a metaanalysis of data from 170,000 participants in 26 randomised trials. Lancet;376:167081. 27. Zhou Z, Rahme E, Pilote L. Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J 2006;151:27381. 28. Mikhailidis DP, Sibbring GC, Ballantyne CM, et al. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin 2007;23:200926. 29. Miller NH, Hill M, Kottke T, et al. The Multilevel Compliance Challenge: Recommendations for a Call to Action: A Statement for Healthcare Professionals. Circulation 1997;95:108590. 30. Kripalani S, Yao X, Haynes RB. Interventions to Enhance Medication Adherence in Chronic Medical Conditions: A Systematic Review. Arch Intern Med 2007;167:5409. 31. Haynes RB, Ackloo E, Sahota N, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008;(2):CD000011.

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