Cardiometabolic Risk (Managing High Risk Patients)


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  • Department of Health Statistics for England, 2002. URL: World Health Organization. Integrated Management of Cardiovascular Risk . 2002.
  • Clinical needs to address in the next decade The adverse effects of the classical CV risk factors, hypercholesterolaemia, hypertension and smoking, are well understood. Our increasing understanding of the pathophysiology of CVD is now defining the importance of a range of new cardiometabolic risk factors. Among these, abdominal obesity, low HDL-C, hypertriglyceridaemia and the hyperglycaemia associated with insulin resistance are all increasingly becoming recognised as major cardiometabolic risk factors. However, it is also important to be aware of the impact of chronic, low-grade inflammation and disturbances in the secretion of bioactive substances from adipose tissue (‘adipokines’), which influence CV structure and function.
  • Abdominal obesity: a major underlying cause of acute myocardial infarction (MI) The INTERHEART Study was a case-control study involving 29,972 participants in 52 countries. The study examined the contribution of various cardiometabolic risk factors to the risk of a first acute MI. The study quantified the relationships between risk factors and acute MI through calculation of the population attributable risk (PAR). PAR measures the proportion of acute MI among those who have the risk factor which would be eliminated if the risk factor were removed. Dyslipidaemia (raised apolipoprotein B/A1 ratio) and smoking were associated with the highest PAR. However, the PAR for abdominal obesity was greater than that for either diabetes or hypertension. Body mass index (BMI) showed a modest correlation with the risk of acute MI, but this was not significant when abdominal obesity was included in a multivariate analysis. Abdominal obesity therefore seems to be an important predictor of adverse CV outcomes in its own right. Yusuf S, et al . Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364 : 937 –9 52.
  • Substantial residual CV risk in statin-treated patients The Medical Research Council/British Heart Foundation (MRC/BHF) Heart Protection Study was one of the landmark trials that have established the place of statins in the management of hypercholesterolaemia. A population of 20,536 patients at high CV risk through the presence of coronary disease, other arterial disease or diabetes were randomly assigned to treatment with simvastatin or placebo for an average of 5 years. The intervention was highly effective, with a significant reduction in the risk of CV events of 24%. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were markedly reduced by treatment with the statin (mean changes from baseline of –1.2 mmol/l [–46 mg/dl] and –1.0 mmol/l [–39 mg/dl], respectively). However, other lipid components, such as TG or HDL-C, impact importantly on CV risk and were changed only slightly in the study (mean changes from baseline of –0.3 mmol/l [–27 mg/dl] and 0.03 mmol/l [1 mg/dl], respectively). We may need to look beyond effects on LDL-C to achieve greater results in the management of overall CV risk. 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.
  • Of CHD events that could be prevented, the greatest proportion occurred from controlling BP among older persons, men, and those with stage 1 hypertension (vs stages 2 and 3) or with ISH (vs IDH or SDH). The number of persons with hypertension needing treatment to prevent one CHD event ranged from 20.5 in men to 38.6 in women when controlled to high normal BP (140/90 mmHg) and 10.7 in men and 21.3 in women when controlled to optimal BP (120/80 mmHg). Wong et al. Am Heart J. 2003; 145: 888-895.
  • For those receiving monotherapy, the most common agents used were blockers of the renin-angiotensin system (RAS; either angiotensinconverting enzyme inhibitors or angiotensin receptor blockers), irrespective of age or ethnicity. Overall diuretics, beta blockers, and calcium channel blockers (CCBs) were the second, third, and fourth most commonly used agents but with similar levels of usage. However, this order changed when stratified by age and ethnicity: beta-blockers were the second most commonly used agents for those 55 years of age, but diuretics and CCBs were more frequently used than beta-blockers among older patients or those of African origin.
  • Cardiometabolic Risk (Managing High Risk Patients)

    1. 1. Managing High Risk Patients
    2. 2. Conclusions • Cardiovascular disease is leading cause of death • Cardiometabolic risk is: – ‘All metabolic and vascular risk factors for CVD’ – Strongly enhanced by abdominal obesity, Type 2 diabetes and insulin resistance – Occurring earlier and more commonly – At least partially preventable or reversible – Especially reduced by loss of excess visceral fat – A priority for early identification and effective management to delay onset of morbidity and reduce premature mortality
    3. 3. Deaths attributed to CVD in Type 2 diabetes Department of Health Statistics for England, 2002. World Health Organization. Integrated Management of Cardiovascular Risk. 2002. 100 80 60 40 20 0 All M F All M F CVD mortality % Premature CVD is main cause of death in Type 2 diabetes General population Diabetes 75 57 38.5 40.4 RIM06/413Date of preparation: August 2006 100 80 60 40 20 0 CVD mortality % 40.4
    4. 4. The Cardiovascular Disease Challenge • In 2007, cardiovascular disease (CVD) caused 34% of deaths in the UK, and killed just over 193,000 people1 • CVD cost the health care system in the UK around £14.4 billion in 20062 • Overall CVD is estimated to cost the UK economy £30.7 billion a year of which 27% is due to productivity losses2 Nationally Customer Actions Taken • NSF for Cardiovascular Disease published in 1999 • Huge investment in waiting list reduction for CABG and PTCA • Multiple and detailed risk modification guidelines including the role of statins • Significant investment in lipid modification per annum (c. £500m per annum)3 • Establishment of Stroke and Cardiac networks to drive best practice and NSF implementation • Significant investment in stop smoking services NOTE: For every one fatality, there are at least two people who have a major non-fatal cardiovascular event. There are over 3 million people living with coronary heart disease or stroke.4 Inpatient cases for CVD across England in 2008/9 were 538,4595 1. 2. 3. Render Report 4. NICE CG67 Lipid Modification Clinical Guidelines Accessed June 2010 5. Inpatients 2008-9
    5. 5. 1. Obesity 2. Hypertension 3. Lipids 4. Hyperglycaemia 5. Smoking
    6. 6. Dealing with CVD requires addressing two areas Managing Modifiable Risk Factors Treating events and their impact 1 2 • Diet • Exercise • Smoking • Hypertension • Lipid management • Angiography • PTCA • CABG • Thrombolysis • Anti-coagulation • Follow-up – Up to 90% of the risk of a first heart attack is due to lifestyle factors that can be changed1 – The Care Quality Commission study ‘Closing the gap’1 highlights the lack of CVD prevention. – NICE Primary prevention of CVD2 • Strategy for identifying people at high risk • Full formal risk assessment for those at high risk • Communication about risk assessment and treatment • Optimisation of all modifiable risk factors • Lipid modification therapy  To deliver more of the potential savings, better performance in managing modifiable risk factors to prevent patients from requiring secondary care intervention Closing the Gap – Tackling Cardiovascular Disease and health inequalities by prescribing statins and stop smoking services, Care Quality Commission, Sept. 2009 Accessed June 2010 NICE CG67 – Lipid Modification – Implementing NICE Guidance, March 2010 Accessed June 2010
    7. 7. Risk factors to address in the future CARDIOVASCULAR DISEASE Classical risk factors Emerging risk factors Abdominal obesity ↓HDL-C ↑TG ↑TNFα,IL-6 ↑PAI-1 ↑Glu ↑IR T2DM ↑Smoking↑ LDL-C ↑ BP ↓ Adipo- nectin RIM06/413Date of preparation: August 2006
    8. 8. Current cardiometabolic risk management approaches • Anti-diabetic agents – Metformin – Sulphonylureas – Glitazones • Lipid modifying agents – Statins – Fibrates – Nicotinic acid • Antihypertensive agents – ACE inhibitors – Angiotensin II receptor antagonists • Weight loss agents – Orlistat
    9. 9. Obesity
    10. 10. Prevalence of adult obesity (BMI >30) in England 0 10 1980 20 30 1986 1991 1996 2000 2010 Prevalence(%) Men Women Kopelman PG. Nature 2000; 404: 635–643; Health Survey for England, 2004; National Audit Office, February 2001; Select Committee on Public Accounts (9th Report), January 2002. % overweight has stayed approx constant since 1993 (M~44%, F~33%) Obesity causes ~30,000 premature deaths annually; 18 million lost working days in 1998 Cost to the nation (including the NHS) > £2.5 billion England 2004 Overweight Obese BMI 25–30 BMI >30 Men 44% 22% Women 34% 23% 2004 RIM06/413Date of preparation: August 2006
    11. 11. Thou seest I have more flesh than another man, and therefore more frailty. William Shakespeare
    12. 12. Abdominal obesity: a major underlying cause of acute myocardial infarction (MI) Populationattributablerisk(%)* * Proportion of MI in the total population attributable to a specific risk factor Cardiometabolic risk factors in the INTERHEART study 0 20 40 60 Hypertension DiabetesAbdominal obesity Dyslipidaemia Abdominal obesity predicts the risk of CVD beyond body mass index (BMI) 18 10 20 49 Yusuf S, et al. Lancet 2004; 364: 937–952. RIM06/413Date of preparation: August 2006
    13. 13. Question: does a waist circumference value of 102 cm and 88 cm distinguish health risk within BMI categories? <88> <102> RIM06/413Date of preparation: August 2006
    14. 14. Metabolic variables in women with low (<88 cm) versus high (>88 cm) waist circumference values Normal weight Overweight Obese Low WC High WC Low WC High WC Low WC High WC Fasting glucose 88 100* 90 100* 84 101* LDL-cholesterol 113 137* 121 139* 118 136* HDL-cholesterol 59 57* 54 54* 58 51* NO DIFFERENCE (n=2959) (n =469) (n =741) (n =1865) (n=38) (n=1467) Triglycerides 97 152* 120 158* 104 161* Systolic BP 115 129* 117 128* 116 128* NHANESIII Janssen I, et al. Arch Intern Med 2002; 162: 2017–2079. RIM06/413Date of preparation: August 2006
    15. 15. Abdominal obesity, morbidity and mortality Intra-abdominal fat is a strong correlate of metabolic risk Intra-abdominal or visceral fat INSIDE Intra-abdominal Fat OUTSIDE Waist Circumference RIM06/413Date of preparation: August 2006
    16. 16. Visceral fat is an independent predictor of all-cause mortality in 291 men followed for 5 years 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Visceral Fat Subcutaneous Fat Waist Circumference CTL/CTS OddsRatiosforMortality Model 2: Control for age, follow-up time, abdominal subcutaneous fat, visceral fat and liver fat Model 1: Control for age + follow-up time 1.8 1.4 1.4 0.8 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Visceral Fat Subcutaneous Fat Waist Circumference CTL/CTS OddsRatiosforMortality 1.8 1.0 0.6 1.3 An 0.37 kg increase in visceral fat is associated with 81% higher mortality after control for SAT and liver fat Kuk JL, et al. Obes Res 2006 14: 336–341. RIM06/413Date of preparation: August 2006
    17. 17. Reduction in abdominal subcutaneous and visceral fat inReduction in abdominal subcutaneous and visceral fat in response to aresponse to a 7%7% exercise-induced weight loss,exercise-induced weight loss, 66 cm reduction incm reduction in waist circumferencewaist circumference Adapted from Ross R,Adapted from Ross R, et alet al.. Ann Intern MedAnn Intern Med 2001;2001;Obes ResObes Res 2004;2004; 1212: 789–798.: 789–798. MENMEN WOMENWOMEN 0 10 20 30 Reduction(%)Reduction(%) ControlControl ExerciseExercise ** ** 0 10 20 30 Reduction(%)Reduction(%) ControlControl ExerciseExercise ** ** Visceral fat Subcutaneous fat **p< 0.05 vs controlp< 0.05 vs control RIM06/413Date of preparation: August 2006 ~5% decrease in waist circumference corresponds to a ~30% decrease in visceral fat!
    18. 18. Potential benefits of 10kg weight loss in individuals of 100kg
    19. 19. Lipids
    20. 20. 20 •Offer statin treatment as part of PRIMARY PREVENTION for adults with a 10 year risk of 20%. •Treat with simvastatin 40 mg. If this is contraindicated or drug interactions are possible, choose a lower dose or an alternative such as Atorvastatin. •Do not routinely offer higher intensity statins—that is, statins used in doses producing greater cholesterol lowering than simvastatin 40 mg (for example, simvastatin 80 mg). [No randomised controlled trials have compared high and low intensity statins in relation to cardiovascular outcomes in people without cardiovascular disease]
    21. 21. Substantial residual CV risk in statin-treated patients Year of follow-up Patientswithmajor vascularevents(%) The MRC/BHF Heart Protection Study Placebo Risk reduction=24% Statin Heart Protection Study Collaborative Group. Lancet 2002; 360: 7–22. BHF=British Heart Foundation MRC=Medical Research Council 10 20 30 0 0 1 2 3 4 5 6 19.8% of statin-treated patients had a major CV event by 5 years p<0.0001 RIM06/413Date of preparation: August 2006
    22. 22. 22 •Use the estimated risk value to prioritise patients, and arrange a full formal risk assessment for patients whose estimated 10 year risk is 20%. •Assess risk using the 1991 Framingham 10 year risk equations, with the following variables: 1. Age (30-74 years) 2. Sex 3. Systolic BP 4. TC 5. HDL 6. Smoking status 7. LVH
    23. 23. 23 •Fasting lipid levels are not needed for risk assessment. •Record factors important for development of CV disease, such as ethnicity, BMI and F/H of premature heart disease. •Adjust the risk score for factors important for development of CV disease but not
    24. 24. included in the risk score as follows: •If there is one first degree relative with premature coronary heart disease, increase the estimate by 1.5; •if there is more than one first degree relative with premature coronary heart disease, increase the estimate by up to 2 •Increase the estimated risk for men with a South Asian background by 1.4.
    25. 25. •Do not set a target concentration for total or LDL cholesterol in primary prevention. •Once a patient has started taking a statin, repeat lipid measurement is unnecessary. Clinical judgment and the patient’s preference should guide the review of drug treatment and whether to review the lipid profile.
    26. 26. 26 Statins for secondary prevention Consider all modifiable risk factors, comorbidities, and secondary causes of hyperlipidaemia, and optimise their management. Offer statin treatment to adults with clinical evidence of CV disease.3 Start treatment with simvastatin 40 mg. If there are potential drug interactions, or simvastatin 40 mg is contraindicated, choose a lower dose or an alternative preparation such as pravastatin. Offer people with acute coronary syndrome a higher intensity statin. [Based on results of health economic modelling of cost effectiveness]
    27. 27. 27 Consider increasing the dose to simvastatin 80 mg or a drug of similar efficacy and acquisition cost if a total cholesterol concentration of <4 mmol/l or a low density lipoprotein cholesterol concentration of <2 mmol/l is not attained Use an "audit" concentration of total cholesterol of 5 mmol/l to assess progress in populations being treated for secondary prevention, as more than half will not achieve a total cholesterol concentration of <4 mmol/l or a low density lipoprotein cholesterol concentration of <2 mmol/l
    28. 28. When generic statins aren’t enough, Atorvastatin has a wealth of cardiovascular evidence Atorvastatin has a wealth of published cardiovascular outcomes trials showing significant primary endpoint benefits: 0Ezetimibe 0Ezetimibe/simvastatin 0Simvastatin 80mg 1Rosuvastatin 8Lipitor Published CV outcomes trials with significant primary endpoint benefit Cholesterol-lowering therapy Atorvastatin has 157 million patient years’ experience worldwide and has been available in the UK for over 10 years There are over 4 million patient-years’ experience worldwide at the 80 mg dose LINK: Quality and Evidence
    29. 29. 30 •nicotinic acid • Omacor • bile acid sequestrants •PPAR agonists • CETP inhibitors •HDL mimetics •ApoA-I mimetic peptides •HDL delipidation and reinfusion
    30. 30. 31 Difficult Hyperlipidaemia Combined hyperlipidaemia Isolated hypertriglyceridaemia Hyperlipidaemia in pregnancy Intolerance to anti lipid agents
    31. 31. In summary Atorvastatin is the statin with the largest evidence base, showing it to be an effective treatment in the management of raised cholesterol and provides a proven reduction in Cardiovascular events Quality Atorvastatin offers the opportunity to make savings now (vs. Ezetimibe) and longer term through windfall savings once it loses exclusivity and there is a price drop. Atorvastatin goes off patent before the other branded lipid lowering agents. Productivity Atorvastatin can help to reduce cardiovascular events by treating to NICE recommended cholesterol levels of 4:2 for diabetes, CHD and stroke patients leading to a productivity gain through avoided spending on events Productivity
    32. 32. Diabetes
    33. 33. In Type 2 diabetes, elevated HbA1c increases risk of complications Stratton IM, et al. BMJ 2000; 321: 405–412. Incidence rate for any end point related to diabetes in males with Type 2 Diabetes Effective glycaemic control is associated with reduced risk of microvascular and macrovascular complications 5 6 7 8 9 10 110 0 20 40 60 80 100 120 140 160 Updated mean HbA1c concentration (%) Adjustedincidenceper 1000personyears(%) RIM06/413Date of preparation: August 2006
    34. 34. Hypertension
    35. 35. BHS classification of blood pressure levels Category Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Optimal BP <120 <80 Normal BP <130 <85 High-normal BP 130-139 85-89 Grade 1 hypertension (mild) 140-159 90-99 Grade 2 hypertension (moderate) 160-179 100-109 Grade 3 hypertension (severe) >180 >110 Isolated systolic hypertension (grade 1) 140-159 <90 Isolated systolic hypertension (grade 2) >160 <90 BHS IV. B Williams et al. J Hum Hyp (2004); 18: 139-185.
    36. 36.     Target organ damage or cardiovascular complications or diabetes or 10 year CVD risk† ≥ 20% >180/110 160−179 100−109 140−159 90−99 130−139 85−89 <130/85 ≥160/100 140−159 90−99 <140/90 No target organ damage and no cardiovascular complications and no diabetes and 10 year CVD risk† <20% * ** *** Treat Treat Treat Observe, reassess CVD risk yearly Reassess yearly Reassess in 5 years *  Unless malignant phase of hypertensive emergency confirm over 1−2 weeks then treat ** If cardiovascular  complications, target organ damage or diabetes is present, confirm over 3−4 weeks then treat; if absent re-measure  weekly and treat if blood pressure persists at these levels over 4−12 *** If cardiovascular complications, target organ damage, or diabetes is present, confirm over 12 weeks then treat: if absent re-measure  monthly and treat if these levels are maintained and if estimated 10 year CVD risk is ≥20% † Assessed with CVD risk chart  THRESHOLDS FOR INTERVENTION Initial blood pressure (mmHg)
    37. 37. Cardiovascular Risk – Non diabetic Men
    38. 38. Cardiovascular Risk – Non diabetic Women
    39. 39. The consequences of not treating hypertension Stroke Heart Attack LVH Renal disease Atrial fibrillation Diabetes
    40. 40. Lowering Blood Pressure Reduces CV Events  • The greatest impact (absolute numbers) from control of hypertension occurs in men, older persons, and those with isolated systolic hypertension. • The greatest proportion of preventable CHD events from control of hypertension occurs in women. • Optimal control of blood pressure could prevent more than one third of CHD events in men and more than half of CHD events in women. Wong et al. Am Heart J. 2003; 145: 888-895.
    41. 41. Lifestyle Measures •Maintain normal weight for adults (body mass index 20- 25 kg/m2 ) •Reduce salt intake to <100 mmol/day (<6g NaCl or <2.4  g Na+ /day) •Limit alcohol consumption to ≤3 units/day for men and  ≤2 units/day for women •Engage in regular aerobic physical exercise (brisk  walking rather  than weight lifting) for ≥30 minutes per  day, ideally on most of days of the week but at least on  three days of the week •Consume at least five portions/day of fresh fruit and  vegetables •Reduce the intake of total and saturated fat  BHS IV. B Williams et al. J Hum Hyp (2004); 18: 139-185.
    42. 42. Hypertension – drug selection [ACD]
    43. 43. In 2006… For those receiving monotherapy the most common agents  prescribed were blockers of the renin-angiotensin (RAS)  system.  Type of drug Age < 55 yr, %  (SE) Age > 55 yr or  Black,       %  (SE) Total % (SE) Diuretics 12 (3.0) 26 (2.1) 23 (1.8) Beta-blockers 33 (4.4) 18 (1.9) 21 (1.8) RAS blockers 41 (4.6) 32 (2.3) 34 (2.0) Calcium  antagonist 14 (3.2) 21 (2.0) 19 (1.7) Other drugs  affecting BP 1 (0.9) 3 (0.8) 3 (0.7) (Falaschetti et al., 2006)Type of Drugs Used, HSE 2006
    44. 44. Compelling and possible indications and contraindications for  major antihypertensive agents (BHS IV) Class of drug Compelling indications Possible indications Caution Compelling  contraindications Alpha-blockers Benign prostatic  hypertrophy Postural hypotension,  heart failure Urinary incontinence ACE inhibitors Heart failure, LV  dysfunction, post MI or  established CHD, Type 1  diabetic nephropathy, 2o   stroke prevention Chronic renal disease,  type II diabetic  nephropathy,  proteinuric renal  disease Renal impairment,  PVD Pregnancy,  renovascular  disease ARBs ACE inhibitor intolerance,  Type II diabetic  nephropathy, hypertension  with LVH, heart failure in  ACE-intolerant patients,  post MI LV dysfunction post MI,  intolerance of other  antihypertensive drugs,  proteinuric renal  disease, heart failure   Renal impairment,  PVD Pregnancy,  renovascular  disease Beta-blockers MI, angina Heart failure Heart failure, PVD,  diabetes (except with  CHD) Asthma/COPD,  heart block  CCBs  (dihydopyridine) Elderly, ISH Elderly, angina CCBs (rate  limiting Angina MI Combination with  beta-blockade Heart block, heart  failure Thiazide-thiazide- like diuretics Elderly, ISH, heart failure  2o  stroke prevention Gout
    45. 45. If a fourth drug is required, one of the  following should be considered: • A higher dose of a thiazide-type diuretic or the addition of another diuretic (e.g. low dose spironolactone) • careful monitoring is recommended • Beta-blockers or • Selective alpha-blockers. If blood pressure remains uncontrolled on  adequate doses of four drugs and expert  advice has not yet been obtained, this should  now be sought. What next after ACD?
    47. 47. Thank you! Visit for more information