Managing High Risk Patients

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

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

0All 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

RIM06/413 Date of preparation: August 2006

100

80

60

40

20

0

CVD mortality

%

40.4

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. http://www.heartstats.org/topic.asp?id=172. http://www.heartstats.org/datapage.asp?id=1013. http://www.productivity.nhs.uk Render Report4. NICE CG67 Lipid Modification Clinical Guidelines http://www.nice.org.uk/nicemedia/live/11982/40689/40689.pdf Accessed June 20105. http://www.hesonline.nhs.uk Inpatients 2008-9

1. Obesity

2. Hypertension

3. Lipids

4. Hyperglycaemia

5. Smoking

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

1. Closing the Gap – Tackling Cardiovascular Disease and health inequalities by prescribing statins and stop smoking services, Care Quality Commission, Sept. 2009http://www.cqc.org.uk/_db/_documents/Closing_the_gap.pdf Accessed June 2010

2. NICE CG67 – Lipid Modification – Implementing NICE Guidance, March 2010 http://www.nice.org.uk/nicemedia/live/11982/40836/40836.ppt Accessed June 2010

Risk factors to address in the future

CARDIOVASCULAR DISEASE

Classical risk factors Emerging risk factors

Abdominalobesity

HDL-C

TG

TNF,IL-6

PAI-1

Glu

IR

T2DM

Smoking LDL-C BP Adipo-nectin

RIM06/413 Date of preparation: August 2006

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

Obesity

Prevalence of adult obesity (BMI >30) in England

0

10

1980

20

30

1986 1991 1996 2000 2010

Pre

vale

nce

(%

)

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

RIM06/413 Date of preparation: August 2006

Thou seest I have more flesh than another man, and therefore more frailty. William Shakespeare 

Abdominal obesity: a major underlying cause of acute myocardial infarction (MI)

Po

pu

lati

on

att

rib

uta

ble

ris

k (%

)*

* 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.RIM06/413 Date of preparation: August 2006

Question: does a waist circumference value of 102 cm and 88 cm distinguish health risk within BMI categories?

<88> <102>RIM06/413 Date of preparation: August 2006

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.

RIM06/413 Date of preparation: August 2006

Abdominal obesity, morbidity and mortality

Intra-abdominal fat is a strong correlate of metabolic risk

Intra-abdominal orvisceral fat

INSIDE

Intra-abdominal Fat

OUTSIDE

Waist Circumference

RIM06/413 Date of preparation: August 2006

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 SubcutaneousFat

WaistCircumference

CTL/CTS

Od

ds

Rat

ios

fo

r M

ort

ali

ty

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 0.80.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Visceral Fat SubcutaneousFat

WaistCircumference

CTL/CTSO

dd

s R

atio

s f

or

Mo

rta

lity

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 fatKuk JL, et al. Obes Res 2006 14: 336–341. RIM06/413 Date of preparation: August 2006

Reduction in abdominal subcutaneous and visceral fat in Reduction in abdominal subcutaneous and visceral fat in response to a response to a 7%7% exercise-induced weight loss, exercise-induced weight loss, 66 cm reduction in cm 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

Re

du

ctio

n (

%)

Re

du

ctio

n (

%)

ControlControl ExerciseExercise

**

**

0

10

20

30

Re

du

ctio

n (

%)

Re

du

ctio

n (

%)

ControlControl ExerciseExercise

**

**

Visceral fatSubcutaneous fat

** p< 0.05 vs controlp< 0.05 vs control

RIM06/413 Date of preparation: August 2006

~5% decrease in waist circumference

corresponds to a ~30% decrease in visceral fat!

Potential benefits of 10kg weightloss in individuals of 100kg

Lipids

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 thansimvastatin 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]

Substantial residual CV risk in statin-treated patients

Year of follow-up

Pat

ien

ts w

ith

maj

or

vasc

ula

r ev

ents

(%

)

The MRC/BHF Heart Protection Study

Placebo Risk reduction=24%

Statin

Heart Protection Study Collaborative Group. Lancet 2002; 360: 7–22.

BHF=British Heart FoundationMRC=Medical Research Council

10

20

30

00 1 2 3 4 5 6

19.8% of statin-treatedpatients had a majorCV event by 5 years

p<0.0001

RIM06/413 Date of preparation: August 2006

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

•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

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.

•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

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

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

http://www.simplyweight.co.uk/forum/forum.php

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

30

•nicotinic acid

• Omacor

• bile acid sequestrants

•PPAR agonists

• CETP inhibitors

•HDL mimetics

•ApoA-I mimetic peptides

•HDL delipidation and reinfusion

31

Difficult Hyperlipidaemia

Combined hyperlipidaemia

Isolated hypertriglyceridaemia

Hyperlipidaemia in pregnancy

Intolerance to anti lipid agents

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

Diabetes

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 1100

20

40

60

80

100

120

140

160

Updated mean HbA1c concentration (%)

Adj

uste

d in

cide

nce

per

1000

per

son

year

s (%

)

RIM06/413 Date of preparation: August 2006

Hypertension

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.

  

Target organ damageor

cardiovascular complicationsor

diabetesor

10 year CVD risk† 20%

>180/110 160 179100 109

140 15990 99

130 13985 89

<130/85

160/100 140 15990 99

<140/90

No target organ damageand

no cardiovascular complicationsand

no diabetesand

10 year CVD risk† <20%

* ** ***

Treat Treat Treat Observe, reassessCVD risk yearly

Reassessyearly

Reassessin 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 INTERVENTIONInitial blood pressure (mmHg)

Cardiovascular Risk – Non diabetic Men

Cardiovascular Risk – Non diabetic Women

The consequences of not treating hypertension

Stroke

Heart Attack

LVH

Renal disease

Atrial fibrillation

Diabetes

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.

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.

Hypertension – drug selection [ACD]

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

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

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?

Refractory Hypertension Drug selection?

• Low renin INCREASED THIAZIDELOOP DIURETIC

SPIRONOLACTONE

• Average renin ALPHA-BLOCKERALPHA-BLOCKER

• High renin BETA-BLOCKERBETA-BLOCKER

ALISKIRENALISKIREN

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