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Diabetic Cardiology: Clinical Updates on Hypertension & Dyslipidemia Therapeutics

Vivian WY LeeAssociate ProfessorSchool of Pharmacy

The Chinese University of Hong Kong11 July, 2010

This Presentation covers:

• Hypertension and DyslipidemiaClinical updates

• Hypertension and diabetes • Dyslipidemia

Clinical Pharmacy Services in Hong

Kong

• AMPOULEPharmacy Innovation

Cardiovascular Risk Factors

Hypertension Cigarette smoking Inactivity

ADyslipidemia Obesity (BMI>30)

Age•>55 for men•>65 for women

Diabetes Mellitus

Microalbuminuria•Or GFR <60mL/min

Family History of Premature CVD•Men <55•Women <65

Introduction Hypertension: important modifiable risk factor for cardiovascular and renal

diseases

Healthy People 2010 (USA): Goal of 50% control rate

JNC-71: 30% unaware of diagnosis; 34% control rate

Hong Kong: 27.2% had hypertension, less than half aware; < 50% control rate 2,3,

Significance of BP Goal Attainment (JNC-71): 16mmHg in SBP associated with 60% in stroke and 50% in

CHD

Stage 1 Hypertension- 12mmHg in SBP X 10 years prevents 1 death in 11 patients

1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood

Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206-1252. 2. Population Health Survey 2003/2004. Comparative Project of Department of Health and Department of Community Medicine, University of Hong Kong 2005: i-ii.3. Cheung BM, Law FC, Lau CP. The Rule of Halves Applies in Chinese Hypertensive Patients. Am J Hypertens 2002; 15: 209A.

AB/CD Algorithm

ACEI/ARB Beta blocker

CCB Diuretics

Renin system: low vs. high

Compelling indications

IndicationIndication DiureticDiuretic --blockerblocker

ACEIACEI ARBARB CCBCCB Aldosterone Aldosterone antagonistantagonist

Heart failureHeart failure

Post MIPost MI

High CAD High CAD riskrisk

DiabetesDiabetes

Kidney Kidney diseasedisease

Recurrent Recurrent stroke stroke preventionprevention

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1. Sookaneknun P, Richards RME, Sanguansermsri J, et al. Pharmacist Involvement in   Primary Care Improves Hypertensive Patient Clinical Outcomes. The Annals of Pharmacotherapy 2004; 38(12): 2023‐8.

2. Hanlon JT, Weinberger M, Samsa GP, et al. A Randomized, Controlled Trial of a Clinical Pharmacist Intervention to Improve Inappropriate Prescribing in Elderly Outpatients With Polypharmacy. The American Journal of Medicine 1996; 100: 428‐37.

3. Planas LG, Crosby KM, Mitchell KD, et al. Evaluation of a hypertension medication therapy management programme in patients with diabetes. Journal of the American Pharmacists Association 2009; 49(2): 164‐70.

4. Lee VWY, Leung PY. Glycemic Control and Medication Compliance in Diabetic Patients in a Pharmacist‐managed Clinic in Hong Kong. American Journal of Health‐System Pharmacy 2003; 60:2593‐6.

CLINICAL IMPACT OF PHARMACY OUTREACH

SERVICE (POS) IN COMMUNITY ELDERLY

PATIENTSPATIENTS

OBJECTIVES

To investigate the impact of POS in the management of hypertension and diabetes;

To evaluate the sustainability of POS beneficial effects

Study Design Prospective, uncontrolled, open labeled study

7 community elderly centres

Started in 2007, Ongoing

Participants

Inclusion Criteria Elderly centre attendees All subjects recruited in

2009 attended Summer Outreach Programme

All subjects recruited in

Exclusion Criteria

With cancer, psychiatric diseases, Parkinson’s or Alzheimer’s disease

All subjects recruited in 2008 included

Uncontrolled HTN1

Non-diabetes: ≥ 140/90 mmHgDiabetes: ≥ 130/80 mmHg

And / OrUncontrolled DM2

> 8mmol/L

Without chronic medications

On other clinical studies

Refusal

1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289(19):2560‐72.2. Chan JCN, Yeung VTF, Chow CC, Ko GTC, Cockram CS, Chan NN. A manual for management of diabetes mellitus: a Hong Kong Chinese perspective. 2nd ed. Hong Kong: Chinese University Press, 2005. p. 24.

Procedures

A total of 3 visits to each centre

Every 10 – 12 weeks

• July 2009 – Sept 20091

Summer Outreach ProgrammeSummer Outreach Programme

• Oct 2009 – Dec 20092

1st follow-up

• Jan 2010 – Mar 20103

2nd follow-up

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Compliance assessment

Disease knowledge assessment

Medication review

Body mass index measurement

Random capillary blood glucose measurement

Blood pressure measurement

Follow‐ups only

Blood pressure measurement

CounselingDrug indication, dosage, frequency, route and time

Goals of therapyDrug-drug/-food/-disease interactions

Adverse drug reactions

Drug storageLifestyle modifications

Disease management

Outcome Measurements

Primary Change in SBP and DBP

Secondary RCBG BMIBMI Compliance HTN, DM knowledge DRPs

Compare between baseline and latest visit Baseline → 1st visit to the subject Latest → last visit to the subject Baseline of disease knowledge, compliance → 1st follow-up

Demographic Data

Mean age = 77.01 ± 6.56

Male : female = 35:62 (36.08%:63.92%)

Age (n=97) Literacy (n=97)

14%

50%

36%

g ( )

60-69 yo70-79 yo≧80 yo

75%

25%

Literate

Illiterate

Demographic Data

Mean no. of chronic meds = 4.93 ± 2.43

Number of chronic medications (n=97)

Self‐purchased medicines / supplements  (n=97)

8%8%

15%

13%

56%

1

2

3

4

≧5

17%

83%

Yes

No

Comparison between Subjects Recruited in 2008 and 2009

60%

70%

80%

90%

100%

Gender

85%

90%

95%

100%

Subjects recruited in 08 (n=40)

Subjects recruited in 09 (n=57)

Smoking

0%

10%

20%

30%

40%

50%

Subjects recruited in 08 (n=40)

Subjects recruited in 09 (n=57)

Female Male

Non/Ex‐smoker Current smoker

75%80%85%90%95%

100%

Subjects recruited in 08 (n=40)

Subjects recruited in 09 (n=57)

Drinking

Non/Ex‐drinker Current drinker

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Interventions Interviews per subject = 2.64

Duration of interview = 30.01 ± 8.37 mins No. of subjects with DRP(s) = 83 (85.57%) Referral notes to physicians issued = 20 (40% acceptance)

Referral notes to physicians

45%

30%

10%

5%5%

5%

p y

Medication change / Adverse drug reactions

Uncontrolled blood pressure

Uncontrolled blood glucose

Laboratory monitoring

Clarification on regimen

Replacement for expired drug

Blood PressureBlood Pressure 

(mmHg), mean ± SDn Baseline Latest Difference

p value

AllSystolic

97152.38 ± 18.80 147.04 ± 20.72 ‐5.35 ± 22.42 0.021

Diastolic 73.84 ± 11.36 71.03 ± 10.97 ‐2.81 ± 10.49 0.010

Recruited  Systolic40

149.31 ± 17.41 145.11 ± 23.93 ‐4.30 ± 25.40 0.290

in 200840

Diastolic 71.77 ± 9.23 69.59 ± 9.52 ‐2.47 ± 11.05 0.165

Recruited in 2009

Systolic57

154.54 ± 19.59 148.33 ± 18.35 ‐6.62 ± 20.53 0.017

Diastolic 75.30 ± 12.52 72.00 ± 11.83 ‐3.16 ± 10.13 0.021

Goal Attained, n(%) n Baseline Latest Difference p value

All 97 14 (14.43) 22 (22.68) +8 (+8.25) 0.096

Recruited in 2008 40 9 (22.5) 10 (25.00) +1 (+2.50) 1.000

Recruited in 2009 57 5 (8.77) 12 (21.05) +7 (+12.28) 0.039

Blood Pressure – Sustainability

110

130

150

170

190

c Blood Pressure 

(mmHg)

Change of Systolic Blood Pressure throughout the 2‐year Study

08/09 1st

08/09 2nd

08/09 3rd

08/09 4th

08/09 5th

08/09 6th

09/10 1st

09/10 2nd

Systolic

Visit

Start of 2008/09 End of 2009/10 Difference p value

Blood Pressure (mmHg)Systolic, mean ± SDDiastolic, Mean ± SD

166.40 ± 20.2279.18 ± 11.79

145.01 ± 23.6369.30 ± 9.57

‐21.39 ± 24.72‐9.88 ± 13.48

<0.001<0.001

Goal Attained, n (%) 0 (0.00) 10 (25.00) 10 (+25.00) 0.002

Random Capillary Blood Glucose

Random Capillary Blood Glucose, mean ± SD

n Baseline Latest Difference p value

All 97 8.41 ± 4.22 8.23 ± 3.96 ‐0.18 ± 4.23 0.670

Goal Attained, n(%) n Baseline Latest Difference p value

All 97 57 (58.76) 59 (60.82) +2 (+2.06) 0.860

Random Capillary Blood GlucoseChange of Random Capillary Blood Glucose throughout the 2‐year Study

0

2

4

6

8

10

12

14

16

m Capillary Blood Glucose 

(mmol/L)

30%

35%

40%

45%

50%

55%

60%

At‐goal Rate

0

08/09 1st

08/09 2nd

08/09 3rd

08/09 4th

08/09 5th

08/09 6th

09/10 1st

09/10 2ndR

andom

Visit

30%

08/09 1st

08/09 2nd

08/09 3rd

08/09 4th

08/09 5th

08/09 6th

09/10 1st

09/10 2nd

Visit

Start of 2008/09 End of 2009/10 Difference p value

Random Capillary Blood Glucose (mmol/dL)

8.86 ± 3.46 9.02 ± 4.14 +0.16 ± 5.25 0.848

Goal Attained, n (%) 14 (35.00) 22 (55.00) +8 (20.00) 0.096

Hypertension KnowledgeHypertension 

Knowledge Score, mean ± SD

n Baseline Latest Difference p value

All 91 6.12 ± 2.14 6.96 ± 1.87 +0.84 ± 1.65 <0.001

Recruited in 2008 37 6.32 ± 2.36 7.24 ± 1.92 +0.92 ± 1.52 0.001

R it d i 2009 54 5 99± 2 01 6 77± 1 82 0 78± 1 74 0 002

Change of Hypertension Knowledge Score

Recruited in 2009 54 5.99 ± 2.01 6.77 ± 1.82 +0.78 ± 1.74 0.002

Recruited in 2008 (n=37)

Recruited in 2009 (n=54)

Difference p value

Hypertension Knowledge, mean ± SD

6.32 ± 2.36 5.99 ± 2.01 0.33 ± 0.46 0.470

Baseline Hypertension Knowledge Score of Subjects Recruited in 2008 and 2009

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Diabetes KnowledgeDiabetes 

Knowledge Score, mean ± SD

n Baseline Latest Difference p value

All 44 6.89 ± 2.34 7.82 ± 2.05 +0.93 ± 1.39 <0.001

Recruited in 2008 22 7.39 ± 2.30 8.41 ± 2.03 +1.02 ± 1.19 0.001

R it d i 2009 22 6 39± 2 31 7 23± 1 94 0 84± 1 59 0 022

Change of Diabetes Knowledge Score

Recruited in 2009 22 6.39 ± 2.31 7.23 ± 1.94 +0.84 ± 1.59 0.022

Recruited in 2008 (n=22)

Recruited in 2009 (n=22)

Difference p value

Diabetes Knowledge, mean ± SD

7.39 ± 2.30 6.39 ± 2.31 1.00 ± 0.70 0.158

Baseline Diabetes Knowledge Score of Subjects Recruited in 2008 and 2009

Drug-related Problems

4%

4%2% 2%

Identified DRP (n=233)

Non‐compliance

Suspected adverse drug reaction

Dosage too low 6%

2%

1%

1%

Noncompliance Identified (n=147)

Misunderstood directions

Missed doses

Fear of adverse d ti

63%10%

10%

5%

4%

Drug storage problem

Need additional drug

Possible interactions

Ineffective drug

Others

61%12%

9%

8% drug reaction

Inappropriate administration

Think no need

Inappropriate pill splitting method

Overuse as needed (PRN) drugs

Drug-related ProblemsNon-compliance: Missed dose

Forgetfulness

Complex regimen

A i i 80 1TAB QDGlibenclamide 5mg 

Aspirin 80mg 1TAB QDMethyldopa 250mg 1TAB BDFamotidine 20mg 1TAB BDCarvedilol 6.25mg 1TAB BDIsosorbide dinitrate 15mg 1TAB TIDEnalapril 10 mg 1TAB OMFluvastatin 80mg 1TAB Nocte

g2TAB AM and 1.5TAB PM

Compliance aids may help1,2

1. Ruppar TM, Conn VS, Russell CL. Medication Adherence Interventions for Older Adults: Literature Review. Research and Theory for Nursing Practice: An International Journal 2008; 22(2): 114‐147.

2. Petersen ML, Wang Y, Van der Laan MJ, et al. Pillbox Organizers Are Associated with Improved Adherence to HIV Antiretroviral Therapy and Viral Suppression: A Marginal Structural Model Analysis. Clinical Infectious Diseases 2007; 45:908–915.

Colour coding Labels Labels with different colours distinguishing different type

of drugs

Labels indicating different time of administration

Completed Drug Diaries Pill Boxes Help elderly with problem of forgetting doses due to

complex drug regimen

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Conclusions

Pharmacy Outreach Service with pharmacist interventions once every 10-12 weeks improved BP control, disease knowledge in elderly with uncontrolled HTN and/or DM.

The beneficial effect of POS is sustainable with regular follow-up visits.

H li id iHyperlipidemia

LIPOPROTEINS

Chylomicrons

Very Low Density Lipoprotein (VLDL-C)

Intermediate Density Lipoprotein (IDL-C)

Low Density Lipoprotein (LDL-C)

High Density Lipoprotein (HDL-C)

Emerging Risk Factors for CHD

Lipoprotien (a) LDL-like moiety + large glycoprotein, Apo (a) Competes with plasminogen for fibrin binding sites---inhibit

fibrinolysis Ability to promote LDL oxidation and inflammation within Ability to promote LDL oxidation and inflammation within

the injured epithelium Has not been shown to respond to dietary fat restriction,

weight loss, or exercise Use of either estrogen or niacin

Homocysteine

By-product of the metabolism of methionine

Require several enzyme and vitamin cofactors, including folic acid, vitamin B12 & B6 for metabolism

Promotion of foam cell formation, LDL oxidation, platelet aggregation, and endothelial dysfunction

Normal level: 5-15 mol/L

Lowered by lifestyle modifications & increasing intake of folic acid, vitamin B12 or B6

C-reactive Protein

An acute phase reactant that is a sensitive marker for systemic inflammation

CRP elevated---at risk for future atherosclerotic events

Microinflammation may cause a stable plaque to rupture and become unstable

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Small, dense LDL Particles

More susceptible to oxidation

Less likely to bind to LDL receptors

Slowly eliminated from plasma

Can easily gain access into the arterial wall due to its small y gsize

Commonly found in patients with hypertriglyceridemia and low HDL

Abnormal subclass (Pattern B) can be treated with niacin or fibric acid derivatives

improved glycemic control

weight loss

CHD Risk Reduction with Lipid Level Changes

Type of Lipid Lipid Level Changes

CHD Risk Reduction

LDL-CLow-density lipoprotein cholesterol

0.026 mmol/L 1 %

cholesterol

TCTotal cholesterol

0.06 mmol/L 2 to 3 %

HDL-CHigh-density lipoprotein cholesterol

0.026 mmol/L 3 %

Source: Holme (1993), Brewer 2004

National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III

CHD Risk Category Minimal LDL-C Goal (1)

Optimal LDL-C Goal (2)

High RiskCHD or CHD risk equivalent , 10-year CHD risk > 20%

< 2.6 mmol/L < 1.8 mmol/L

d l i h i k 3 4 l/ 2 6 l/Moderately High Risk2+ risk factors,10-year CHD risk 10 to 20%

< 3.4 mmol/L < 2.6 mmol/L

Moderate Risk2+ risk factors,10-year CHD < 10%

< 3.4 mmol/L -

Low Risk0 – 1 risk factor

< 4.1 mmol/L -

(1) NCEP ATP III 2001, (2) Grundy et al 2004

Clinical Impact of Clinical Pharmacy Services on

Hyperlipidemia Management –H K E iHong Kong Experience

Chung JS, Lee KKC, Tomlinson B, Lee VWY. Journal of Cardiovascular Pharmacology and Therapeutics ( In press)

Objective of Study

To evaluate the clinical benefits of apharmacist clinical service for themanagement of hyperlipidemia in anambulatory setting of public hospitalin Hong Kong

Methodology of Study

Chinese patients > 18yearsMale or Female

History of hyperlipidaemia or CHD

Approved by the Clinical Research Ethics Committee of CUHKOutpatient Lipid Clinic, Prince of Wales Hospital

24-months study period

Control Group Intervention GroupControl Group(n = 150)

Routine Physician Care

Intervention Group(n = 150)

Routine Physician CarePharmacist Intervention

Educational Visits (every 16 to 26 weeks)

Monthly Telephone Follow-Ups

CHD risk assessment (Framingham point scores), Lipid profilereviews (NCEP ATP III 2001), Healthy lifestyle advice, Drugeducation, Medication compliance via pill-counting, Additional adviceon comorbidities

Both Groups: Validated Questionnaire Survey on

CPS Implementation before and after study.

Physicians’ view of CPS

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Demographic Data

Characteristics Intervention Group (n = 150)

Control Group

(n = 150)

P value

( ) ( ) ( ) ( )Age (years), mean (SD) 56.2 (10.4) 57.9 (12.9) ns

Sex (male), n (%) 68 (45.3) 60 (40.0) ns

Hypertension, n (%) 76 (50.7) 78 (52.0) ns

Diabetes mellitus, n (%) 40 (26.7) 43 (28.7) ns

Hypertension & Diabetes mellitus,n (%)

29 (19.3) 30 (20.0) ns

Lipid Profile Changes in Intervention and Control Groups Before & After the Study

Intervention Group(n = 150)

Control Group(n = 150)

BaselineMean (SD)

End of StudyMean (SD)

BaselineMean (SD)

End of StudyMean (SD)

LDL-C (mmol/L)

3.53 (1.30) 2.60 (0.89) 3.48 (1.35) 3.04 (1.17)

(mmol/L)

HDL-C (mmol/L)

1.60 (0.41) 1.72 (0.46) 1.63 (0.50) 1.69 (0.55)

TC (mmol/L)

6.05 (1.41) 5.00 (0.93) 5.91 (1.27) 5.52 (1.26)

TG (mmol/L)

2.20 (1.72) 1.54 (1.06) 2.08 (1.24) 1.84 (1.57)

Low-density lipoprotein cholesterol (LDL-C), High-density lipoprotein cholesterol (HDL-C), Total cholesterol (TC),Triglycerides (TG)

Comparison of Lipid Profile Changes between Intervention & Control Groups at end of study

Mean % ChangeIntervention

Group (n = 150)

Mean % Change Control Group

(n = 150)

P value

LDL-C (mmol/L) - 23.63 (0.12) - 3.71 (0.40) < 0.001LDL C (mmol/L) 23.63 (0.12) 3.71 (0.40) 0.001

HDL-C (mmol/L) + 8.83 (0.14) + 4.74 (0.10) ns

TC (mmol/L) - 15.25 (0.10) - 5.20 (0.12) < 0.001

TG (mmol/L) - 22.33 (0.16) - 2.70 (0.33) < 0.001

Low-density lipoprotein cholesterol (LDL-C), High-density lipoprotein cholesterol (HDL-C), Total cholesterol (TC),Triglycerides (TG)

Potential CHD Risk Reduction in Study

Mean Reduction Potential CHD Risk Reduction

Control Group

LDL C level 0 44 mmol/L 16 9%LDL-C level 0.44 mmol/L 16.9%

Intervention Group

LDL-C level 0.93 mmol/L 35.8%

Summary

Overall lipid mean reduction was more in intervention group LDL-C level 7 times more than control group TC level 3 times more than control group TG level 10 times more than control groupg p

Control group showed a lipid-lowering effect with current hyperlipidaemic management

Addition of pharmacist improved lipid-lowering effect further and more patients achieved LDL-C goals

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http://www.pharmacy.cuhk.edu.hk/ampoule/

TEAM WORK

Acknowledgement

Collaborators Prof. Brian Tomlinson (Department of Medicine & Therapeutics, CUHK) Dr. Celeste Ewig (School of Pharmacy, CUHK) Pharmaceutical Society of Hong Kong CUHK School of Pharmacy Alumni Association Sik Sik Yuen Ho Chui District Community Centre for Senior Citizens;

Sh K H i W lf C il Ch k Y C M ti Di t i t Eld l C it Sheng Kung Hui Welfare Council Chuk Yuen Canon Martin District Elderly Community Centre and Sheng Kung Hui Welfare Council Wong Tai Sin District Elderly Community Centre;

Yang Memorial Methodist Social Service Choi Hung Community Centre for Senior Citizens;

Tseung Kwan O Aged Care Complex – Jockey Club District Elderly Community Centre Vicwood K. T. Chong Neighbourhood Elderly Centre Social Welfare Department, Hong Kong Special Administrative Region

Funding Agency Knowledge Transfer Project Fund, University Grant Committee

Thank You!