Pharmacy Perspectives: Dyslipidemia

1
Pharmacy PerspectivesDyslipidemia

• An Interactive Module

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Disclaimer

• The information presented in the Pharmacy
  Perspectives Dyslipidemia program and materials
  was prepared by independent physicians and
  pharmacists through an educational grant provided
  by the sponsor, AstraZeneca Canada Inc., and does
  not necessarily reflect the opinions or views of
  the sponsor or the publisher.
• Health care professionals should consult approved
  prescribing information for complete product
  information and should take into account the
  individual patient's specific medical history
  when using the materials to diagnose, treat or
  otherwise care for patients.
• Sponsor does not endorse the use of any product
  other than in accordance with approved
  prescribing information once product has been
  approved.

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Learning Objectives

• Review the role of cholesterol in atherosclerosis
  
• Discuss the implication of the evolving
  recommendations in lipid management
• Importance of LDL-C and the TC/HCL-C ratio
  targets
• Patient risk-benefit profile
• Focus on statins
• Demonstrate the efficacy of statins to reach
  various lipid targets (LDL-C, TC/HDL-C) and
  reduce adverse cardiovascular events
• Discuss safety issues regarding statins
• Class effects of statins focus on muscle and
  liver side effects
• Mechanisms of action of statins and the relevance
  of drug interactions
• Discuss the role of pharmacists in patient
  adherence to therapy
• Communication techniques
• Programs available to enhance patients adherence

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Patient Profile

• Ms. Lesley is a 58-year-old Caucasian, secretary
  who just went for her annual check-up
• She is a non-smoker now she used to smoke a
  pack a day and quit one year ago
• Her father died at age 50 of a heart attack, so
  she needs to do everything she can to stay
  heart-healthy
• Ms. Lesley has been taking a diuretic
  (hydrochlorothiazide 25 mg) every day. Her blood
  pressure is 140/85 mm Hg
• Dr. Chow sent Ms. Lesley for some routine blood
  work

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The Patient Pharmacy Visit 1

• Ms. Lesley presents to the pharmacy after
  receiving the results of the lab test and
  visiting her doctor. She asks the pharmacist
  about the usefulness of her statin prescription.
  She feels well and is concerned about taking this
  new medication
• What is my risk of heart attack? Will I need to
  take this pill forever?

How do you explain to this patient what
cholesterol is and the consequences of not taking
her prescribed medication?
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Cholesterol

• Necessary for the formation of
• bile acids
• cell membranes
• steroid hormones
• 75 synthesized by body
• (mostly liver)
• 25 obtained from diet
• Insoluble in water, transported as lipoproteins
  (LDL, HDL, VLDL)

http//www.americanheart.org/presenter.jhtml?ident
ifier180 accessed March 8, 2007
7
Cholesterol Fractions
McPherson R, Frohlich J, Fodor G, Genest J.
Canadian Cardiovascular Society position
statement Recommendations for the diagnosis and
treatment of dyslipidemia and prevention of
cardiovascular disease. Can J Cardiol
200622(11)913-927.
8
Pathophysiology of Atherosclerosis
Stary et al. Cir 199592(5)1355-74.
9
Relationship Between Changes in LDL-C and HDL-C
Levels and CHD Risk
Pederson TR et al. Circulation 1998971453-1460
10
Cholesterol Treatment Trialist Collaboration
Findings

• Prospective meta-analysis from 90,056 patients in
  14 randomized trials of statins demonstrated
• Decreasing LDL-C with a statin by 1 mmol/L in
  patients with and without established
  cardiovascular disease, decreased the following
• All cause mortality 12
• CHD 19
• Major vascular event 21
• Non-fatal MI 26
• CHD death 19
• Need for revascularization 24
• Stroke 17

Lancet 20053661267-78
11
Implications for the Management of Lipids

• When risk is very high, a lower LDL-C goal is a
  better therapeutic option, a reasonable clinical
  strategy, on the basis of available clinical
  trial evidence

Grundy SM, et al. JAM Coll Cardiol 200444720
12
Deaths From Selected Causes in Canada
Statistics Canada, Canadian Vital Statistics,
Deaths Database Demography Division, 2001
13
Lifetime Risk of Developing CHD is High
CHDcoronary heart disease MImyocardial
infarction, Angina, coronary insufficiency, MI,
or coronary death Adapted from Lloyd-Jones DM et
al. Lancet 19993538992.
14
Patient Profile

• If Ms. Lesleys lab results are
• TC 6.15 mmol/L
• TC/HDL-C 6.0
• HDL-C 1.02 mmol/L
• LDL-C 4.6 mmol/L
• TG 1.9 mmol/L
• Glucose 5.3 mmol/L

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Question

• How would you assess Ms. Lesleys individual
  risk?

What tools are available to assess patients risk?
16
NCEP Risk Factors in Primary Prevention

• Positive Risk Factors
• Age
• Male 45 years
• Female 55 years or premature menopause with ERT
• Family history of premature CHD
• Current cigarette smoking
• Systolic Blood Pressure 130 mmHg (non-treated)
  or 120 mmHg (treated)
• Low HDL-C (lt1.3 mmol/L)
• Diabetes mellitus
• High LDL-C (4.14 mmol/L depending on age and sex)
• Negative Risk Factors
• High HDL-C (gt1.55 mmol/L)

17
What is Framingham Risk Score?

• The new Canadian Cardiovascular Society position
  statement Recommendations for the diagnosis and
  treatment of dyslipidemia and prevention of
  cardiovascular disease
• Recommended for the initial assessment of the
  majority of patients in the primary prevention
  category
• The Framingham risk estimate tables adjust for
  certain risk factors such as TC and smoking
  status for age, and correct for the effects of
  treatment on blood pressure measurement
• Provides an estimate of the 10-year risk estimate
  of hard cardiac end points

Can J Cardiol 200622(11)913-27.
18
Question

• Using the Framingham risk assessment, what is Ms.
  Lesleys risk of cardiovascular event in the next
  10 years?

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Framingham Score Card Female 10-year risk of
CVD
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Question

• The patient has been prescribed a statin and
  asks
• Do I really need that prescription?
• I am wondering if I must take this pill for the
  rest of my life
• How would you counsel her?

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2006 Recommendations for the Diagnosis and
Treatment of Dyslipidemia and Prevention of
Cardiovascular Disease
Risk Categories and Treatment Recommendations
High risk includes coronary artery disease
(CAD), peripheral artery disease, cerebrovascular
disease (CVD) and most patients with diabetes.
Individuals younger than 40 years with
recent-onset diabetes, a normal lipid profile and
no require immediate lipid-lowering therapy. In
patients with established atherosclerosis,
treatment to lower low-density lipoprotein
cholesterol (LDL-C) by at least 50 is generally
appropriate Apolipoprotein B may be used to
determine CAD risk, especially in
hypertriglyceridemic patients, and monitor
adequacy of treatment. Optimal levels of
apolipoprotein B are less than 0.85 g/L in
high-risk patients less than 1.05 g/L in
intermediate-risk patients and less than 1.2 g/L
in low-risk patients Treatment may be
initiated at lower or higher levels if family
history or other investigations include elevated
or reduced risk. Patients with severe genetic
lipoprotein disorders such as familial
hypercholesterolemia or type 3 dyslipidemia
should be treated because of their high risk of
premature CAD Patients in low- or
moderate-risk categories may be at high long-term
cardiovascualr risk. This group includes many
patients with abdominal obesity (the metabolic
syndrome). The reduction in CAD and stroke
events, and overall cost-effectiveness of therapy
is proportional to the decrease in LDL-C. Thus,
for those low- or moderate-risk subjects who are
candidates for statin therapy, treatment to lower
LDL-C by at least 40 is generally appropriate.
HDL-CHigh-density lipoprotein cholesterol
TCTotal cholesterol
McPherson R, Frohlich J, Fodor G, Genest J.
Canadian Cardiovascular Society position
statement Recommendations for the diagnosis and
treatment of dyslipidemia and prevention of
cardiovascular disease. Can J Cardiol
200622(11)913-927.
22
Canadian Lipid Targets for Patients at CV risk
(2003)
Risk categories and target levels
Jacques Genest et al. Recommendations for the
management of dyslipidemia and the prevention of
cardiovascular disease 2003 update. CMAJ.
2003168921-4.
23
Family History

• For patients with a family history of CAD in a
  first degree relative younger than 55 years (men)
  or 65 years (women), the calculated 10-year CAD
  risk should be multiplied by a factor of 2.0
  (class I, level C)
• Does this change Ms. Lesleys Framingham Risk
  Score?

McPherson R, Frohlich J, Fodor G, Genest J.
Canadian Cardiovascular Society position
statement Recommendations for the diagnosis and
treatment of dyslipidemia and prevention of
cardiovascular disease. Can J Cardiol
200622(11)913-927.
24
Recommendations for the Diagnosis and Treatment
of Dyslipidemia and Prevention of Cardiovascular
Disease

• New clinical data have emerged that support a
  more vigorous approach to lipid lowering
• Primary treatment targets LDL-C
• Secondary treatment targets TC/HDL-C

McPherson R, Frohlich J, Fodor G, Genest J.
Canadian Cardiovascular Society position
statement Recommendations for the diagnosis and
treatment of dyslipidemia and prevention of
cardiovascular disease. Can J Cardiol
200622(11)913-927.
25
TCHDL-C Ratio

• A simple test that encompasses the CAD risk
  associated with both elevated LDL-C and reduced
  HDL-C1
• One of the 2 key treatment priorities in the
  current 2006 Canadian positioning statement2 and
  detailed on the majority of laboratory lipid
  profiles
• The best predictor of CAD, demonstrated in
• Québec Cardiovascular Study 20001
• The landmark Framingham Study3
• Cholesterol and Coronary Heart Disease Study4

• Després JP, et al. Atherosclerosis
  2000153(2)263-272. 2. Genest J, Frolich JJ,
  CMAJ 2003169(9)..
• McPherson R, Frohlich J, Fodor G, Genest J.
  Canadian Cardiovascular Society position
  statement Recommendations for the diagnosis and
  treatment of dyslipidemia and prevention of
  cardiovascular disease. Can J Cardiol
  200622(11)913-927.
• Kannel WB. J Atheroscler Thromb 20006(2)60-66.
  4. Kinosian B, et al. Ann Intern Med
  1994121641-647.
• Kinosian B, Glick H, Garland G. Cholesterol and
  coronary heart disease predicting risks by
  levels and ratios. Ann Intern Med
  1994121641-647.

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Question

• Why is aggressive lipid lowering important in Ms.
  Lesleys case?

27
LDL-C Lowering and the associated reduction of
CV outcomes
Fitchett DH, Leiter LA, et al. Can J Cardiol
20052185-90
28
Ischemic Heart Disease (IHD)Risk and the
TC/HDL-C Ratio
Lemieux I, et al. The Québec Cardiovascular
Study. Arch Intern Med 20011612685-2692.
29
Patient Question

• Ms. Lesley asks if there is a difference between
  this type of medication in terms of lowering her
  bad cholesterol.

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Canadian Recommendations

• The 2006 Canadian recommendations for the
  diagnosis and treatment of dyslipidemia and
  prevention of cardiovascular disease indicate
• Low-Moderate risk patients should lower LDL-C by
  at least 40
• High risk patient should lower LDL-C by at least
  50
• What agents can achieve this target?

McPherson R, Frohlich J, Fodor G, Genest J.
Canadian Cardiovascular Society position
statement Recommendations for the diagnosis and
treatment of dyslipidemia and prevention of
cardiovascular disease. Can J Cardiol
200622(11)913-927.
31
Effect of Statins on LDL-C, HDL-C and TGi
Significantly different (plt0.002) compared with
(a) Rosuvastatin 10 mg, (b) Rosuvastatin 20
mg,(c) Rosuvastatin 40 mg
iJones P, et al. for the STELLAR Study Group.
Comparison of the Efficacy and Safety of
Rosuvastatin Versus Atorvastatin, Simvastatin,
and Pravastatin Across Doses (STELLAR Trial). Am
J Cardioll 2003 92 152-160.
32
Rosuvastatin vs Comparators LDL-C Efficacy at
Low Dose - The STELLAR Study
plt0.002 vs atorvastatin 10 mg simvastatin 10,
20, 40 mg pravastatin 10, 20, 40 mg plt0.002 vs
atorvastatin 20, 40 mg simvastatin 20, 40, 80
mg pravastatin 20, 40 mg plt0.002 vs
atorvastatin 40 mg simvastatin 40, 80 mg
pravastatin 40 mg
Adapted from Jones PH et al. Am J Cardiol
200392152160
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Statins TC/HDL-C Ratio Efficacy Across the Dose
Range
plt0.002 vs equivalent parts of the authorized
doses of comparators
Jones PH, et al. for the Statin Therapies for
Elevated Lipid Levels compared Across doses to
Rosuvastatin (STELLAR) Study Group. Effects of
rosuvastatin versus atorvastatin, simvastatin,
and pravastatin on non-high-density lipoprotein
cholesterol, apolipoproteins, and lipid ratios in
patients with hypercholesterolemia Additional
results from the STELLAR trial. Clinical
Therapeutics 200426(9)1388-1399.
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Lifestyle

• All individuals should be encouraged to adopt a
  healthy lifestyle to lower their risk of CAD
  (Class I, level A)
• Smoking cessation
• Achievement and maintenance of ideal body weight
• Regular exercise
• Limit intake of saturated and trans fatty acids
  and simple sugars

McPherson R, Frohlich J, Fodor G, Genest J.
Canadian Cardiovascular Society position
statement Recommendations for the diagnosis and
treatment of dyslipidemia and prevention of
cardiovascular disease. Can J Cardiol
200622(11)913-927.
35
Statins Therapeutic Safety Monitoring
36
Patient Counselling

• How do you counsel a patient when they receive a
  statin prescription for the first time?

• What should they watch for with statins?

37
Current Overview of Statin-Induced Muscle Side
Effects
Pasternak Use and Safety of Statins. J AM Coll
Cardiol 200240567-72.
38
Factors that Increase the Risk of Statin-Induced
Myopathy
Rosenson RS, Current Overview of Statin-Induced
Myopathy. AM J Med. 2004116408-416.
39
Statin Monitoring and Goals of Therapy
Statin Monitoring and Goals of Therapy. A
Reference Guide. ACC Tool.
40
Key Points to Discuss with Patients

• Repeat cholesterol blood test approximately 6
  weeks after starting therapy
• Have liver enzymes (AST/ALT) checked during your
  initial blood test (baseline), 3 months and then
  annually
• Let your physician know if you experience muscle
  pain
• Inform your physician about baseline muscle
  complaints
• Any change in severity or sensation let your
  physician know
• Especially if you experience fever or
  cola-coloured urine
• Pregnancy (are or intend to become)
• Significant consumption of alcohol

McPherson R, Frohlich J, Fodor G, Genest J.
Canadian Cardiovascular Society position
statement Recommendations for the diagnosis and
treatment of dyslipidemia and prevention of
cardiovascular disease. Can J Cardiol
200622(11)913-927.
41
Question

• Ms. Lesley complains of muscle pain
• How do you address this complaint?

42
Myalgias

• The ability of statins to produce myopathy under
  some circumstances is well established. A common
  complaint is non-specific muscle aches or joint
  pains that are generally not associated with
  significant increase in creatinine kinase.
• A recent prospective meta-analysis of 35 trials
  including 74 102 patients designed to assess the
  harm associated with statins demonstrated that
• Statin therapy (excluding cerivastatin) did not
  result in a significant increase in
  myalgiasRisk/1000 patients 2.7 95 CI, -3.2
  to 8.7

Paternak et al. JACC, 40(3)576-72, Kashani A,
Circulation 2006 114 2788-2797
43
Benefit Versus Risk for Various StatinsLDL-C
Reduction Versus CK Elevation
Brewer HB Jr. Am J Cardiol 200392(suppl)23K-29K
44
Benefit Versus Risk for Various StatinsLDL-C
Reduction Versus Effect on ALT
3.0
2.5
2.0
Occurrence ofALT gt3ULN ()
1.5
1.0
0.5
0.0
20
30
40
50
60
70
LDL-C reduction ()
Brewer HB Jr. Am J Cardiol 200392(suppl)23K-29K
45
The Patient Visit 2

• The patient returns to the pharmacy a few weeks
  later with a prescription for clarithromycin,
  which has been prescribed for bronchitis.
• The patient returns to the pharmacy a few weeks
  later with a prescription for diltiazem.

46
Questions

• What do you need to be aware of with those
  patients who are on statins?

What do you need to know about a patient who is
taking a statin and prescribed something new?
What key questions should you ask the patient?
How should you advise Ms. Lesley specifically in
terms of drug interactions?
47
Pharmacokinetic Comparison of the Statins
48
First Pass Effect Pre-systemic Metabolism
Mediated by CYP 3A4
N Engl J Med 20053522211-21.
49
Drug Interactions with Statins
No represents no interaction Yes represents an
interaction Although no drug interactions were
observed when rosuvastatin was coadministered
with fenofibrate or niacin, the combination of a
statin and a fibrate or niacin should be
cautiously implemented due to the potential
increase in skeletal muscle effects. This is also
true for pravastatin. Increased systemic
exposure to rosuvastatin has been observed in
subjects taking concomitant rosuvastatin and
gemfibrozil. Patients taking this combination
should receive low-dose rosuvastatin 10 mg once
daily and should not exceed a dose of 20 mg once
daily. In a clinical trial, a trend toward
CPK elevations and musculoskeletal symptoms was
seen in patients treated concurrently with
pravastatin and gemfibrozil. Contraindicated
50
Fenofibrate-Statin Combination Reports of
Rhabdomyolysis
FDAs Adverse Events Reporting System
Jan/1998-Mar 2002
Jones PH, Am J Cardiol 200595120-122
51
Fibrates and Rosuvastatin

• Co-administration of fenofibrate and rosuvastatin
  10mg did not lead to a clinically significant
  change in the plasma concentrations of either
  drug
• In addition, neither myopathy nor marked CK
  elevations were observed in a study of 103
  patients who received rosuvastatin 5 mg and
  rosuvastatin 10mg plus fenofibrate
• Based, on the above data, no pharmacokinetic or
  pharmacodynamic interaction was observed

Martin, Paul D et al. An Open-Label, Randomized,
Three-Way Crossover Trial of the Effects of
Coadministration of Rosuvastatin and Fenofibrate
on the Pharmacokinetic Properties of Rosuvastatin
and Fenofibric Acid in Healthy Male Volunteers.
Clin Ther., 200325459-471
52
Initial and Continuous Counselling

• How can the pharmacist help and improve adherence
  to treatment and accomplish this role effectively?

Patient non-adherence is a substantial obstacle
to the achievement of therapeutic goals
53
New Patients Remaining on Cholesterol-Lowering
Medication Since First Prescription (n11,000)
From Saskatchewan Prescription Drug Plan, 1995
54
Strategies for Enhancing Patient Compliance

• Practical Interventions
• Improve patients level of information concerning
  the specifics of their prescription and disease
• Take clinically appropriate steps to reduce the
  cost, complexity, duration and amount of
  behavioural change required
• Arrange for the continued monitoring of the
  patients compliance to treatment

Becker MH, Maiman LA, Jour of Community Health
19806(2)113-135
55
Strategies for Enhancing Patient Compliance

• Practical Interventions
• Increase healthcare team awareness of non
  compliance and develop an active influence
  orientation attitude
• Involve the patient in therapeutic decisions
• Involve fully the assistance of all available
  health care providers (improving adherence to
  treatment)

Becker MH, Maiman LA, Jour of Community Health
19806(2)113-135
56
Conclusions

• Educate patients on the role of cholesterol,
  their personal target (LDL-C TC/HDL-C) and the
  benefits of decreasing CV risk
• Involve the patient in the treatment plan
• Balance discussion on risk benefits of the
  treatment
• Non pharmacologic strategies (diet exercise)
  are also important
• Stress the importance of long term therapy
• Carefully monitor and regularly council patient
  on potential side effects of statins and not only
  on the first prescription
• Continued care

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Key Take-away Learning Points

• The goal of therapy should be on safely achieving
  lipid levels as defined by the current Canadian
  Position Statement to protect patients and ensure
  they are well informed
• Recent studies indicate that lower LDL-C goals
  may be preferred for high risk patients
• Drug interactions are common with statins and may
  not necessarily require treatment to be
  discontinued but needs to be evaluated as part of
  continued care
• Serious myopathy or rhabdomyolysis is very rare,
  but may be fatal. Pharmacists should be aware of
  risk factors for this complication and should
  screen and refer patients back to the physician
• Adherence could be improved with proper
  interventions