Transcript Supplemental Content - Annals of Internal Medicine

© 2015 American College of Physicians
The information contained herein should never be
used as a substitute for clinical judgment.
BEYOND THE GUIDELINES:
A 67-year-old woman considering treatment for hyperlipidemia
Medicine Grand Rounds
February 12, 2015
Discussants
BIDMC Series Editor
Moderator
Murray Mittleman,
MD, DrPH
Risa Burns, MD,
MPH
Gerald Smetana,
MD
William Taylor, MD
The Series Editors have no conflicts of interest to disclose.
Conflict of Interest Disclosure:
The speakers have no financial relationships
with a commercial entity producing
healthcare-related products and/or services.
Risa Burns, MD, MPH
Murray Mittleman, MD, DrPH
William Taylor, MD
Gerald Smetana, MD
OUR PATIENT
Medical History
 Ms T is a 67-year old woman with history of hypertension
 In 2009, her total cholesterol was 286 mg/dL and her HDL was
62 mg/dL. Using ATP III Guideline to guide treatment decisions:
 LDL was 203 mg/dL
 2 risk factors (age and hypertension)
 Framingham tables - 10 year risk of a CHD event was 5%
 ATP III Guideline suggested consideration of drug therapy
 In consultation with her PCP, opted for therapeutic lifestyle
change given her high HDL
OUR PATIENT
Medical History (cont.)
 Ms T began walking regularly and tried to follow a
heart healthy diet
 In 2012, total cholesterol 283 mg/dL, HDL 75
mg/dL and LDL 181 mg/dL
 In consultation with her PCP, they planned to
continue with therapeutic lifestyle change
OUR PATIENT
Medical History (cont.)
 At Ms T’s most recent visit, total cholesterol 293
mg/dL, HDL 110 mg/dL and LDL 166 mg/dL
 Using pooled cohort equation, 10-year risk of an
ASCVD event was 11.2%
 The ACC/AHA Guideline recommends starting a
moderate to high intensity statin
OUR PATIENT
Past Medical History
 Hypertension since 2009
 Psoriasis
 B12 deficiency
OUR PATIENT
Social History
 Retired
 Lives alone
 Walks regularly
 Eats a heart healthy diet
 No tobacco or alcohol use
OUR PATIENT
Medications
 Hydrochlorothiazide 25mg daily
 Potassium Chloride ER 20mEq daily
 Cyanocobalamin 1000 mcg/mL monthly
 Clobetasol cream 0.05% as needed
 Vitamin D3 1000 units once daily
OUR PATIENT
Physical Examination
 Well appearing
 BP 144/86
 Weight 104 pounds and BMI 21.4
 The remainder of her exam was normal
MS T’S STORY
THE GUIDELINE:
Treatment of Blood Cholesterol to Reduce Atherosclerotic
Cardiovascular Disease Risk in Adults:
THE GUIDELINE:
Treatment of Blood Cholesterol to Reduce Atherosclerotic
Cardiovascular Disease Risk in Adults:
 The NHLBI initiated the ACC/AHA collaboration with the goal
of using data from RCTs, systematic reviews and meta-analysis
to update the clinical practice guidelines for the treatment of
blood cholesterol.
 The recommendations are intended to provide a strong
evidence-based foundation for primary and secondary
prevention of ASCVD.
THE GUIDELINE:
Recommendations for all patients
 Physicians should encourage all patients to adhere to
 Heart healthy diet
 Regular exercise
 Avoidance of tobacco products
 Maintenance of an ideal weight
 Initiate drug treatment for related risk factors including
hypertension and diabetes
THE GUIDELINE:
Four Statin Benefit Groups
 Strong RCT evidence shows that the reduction in ASCVD events from
statin therapy exceeds adverse events for 4 patient groups:
 Secondary Prevention: Clinical ASCVD
 Primary Prevention: LDL-C > 190
 Primary Prevention: Age 40-75 years with diabetes and LDL-C 70189
 Primary Prevention: Age 40-75 years, with an LDL-C 70-189 mg/dL
and an estimated 10-year risk > 7.5%
 Moderate evidence supports consideration of statin therapy for
primary prevention in individuals with an estimated 10-year risk of 5 to
< 7.5%
THE GUIDELINE:
No Benefit
 No benefit to treatment with statins for patients
 NYHA class II, III or IV heart failure OR
 Receiving maintenance hemodialysis
 No benefit to treatment with non-statin therapies
for any patient
THE GUIDELINE
Estimating Risk - Pooled Cohort Equation
 New Pooled Cohort Equation best available method for estimating 10year ASCVD risk
 Advantages of using Pooled Cohort Equation:
 Developed from studies that reflect the risk profile of the general
population
 Includes risk of non-fatal and fatal MI and non-fatal and fatal stroke
 Provide sex- and race- specific ASCVD risk estimates
 Disadvantage some studies observed overestimation of ASCVD risk
THE GUIDELINE:
Estimating Risk - Pooled Cohort Equation
http://tools.cardiosource.org/ASCVD-Risk-Estimator
Used with permission of the American College of Cardiology. Published jointly by ACC and AHA | © 2014.
THE GUIDELINE:
Initiate Appropriate Intensity Statin to Reduce ASCVD Risk
THE GUIDELINE:
Intensity of Statin Therapy
 High intensity statin therapy (LDL-C level decreased by > 50%)
 atorvastatin 40 to 80mg
 rosuvastatin 20 to 40mg
 Moderate intensity statin therapy (LDL-C level decreased by 30
< 50%)
 atorvastatin 10 to 20mg
 rosuvastatin 5 to 10mg
 Simvastatin 20-40mg
 Pravastatin 40mg
 Consider moderate intensity statin in those over 75 years of
age or those with safety concerns
THE GUIDELINE:
Fixed Dose Treatment
 Once appropriate intensity statin is initiated a fasting
lipid panel should be performed
 However, lipid panel results should not be used as a
treatment goal or performance measure
 “Treating to Goal” may result in suboptimal statin
intensity or the addition of non-statin therapy in the
absence of RCT evidence
 Routine monitoring of hepatic aminotransferase levels
or creatine kinase levels is also not recommended
THE GUIDELINE:
Shared Decision Making in Primary Prevention
 Decision to initiate statin therapy in primary prevention
should be based on clinical judgment and patient
preferences.
 Remember that as the absolute risk of an ASCVD event
decreases so does net benefit of treatment.
 It is therefore important to consider:
 potential ASCVD event reduction
 adverse effects
 drug interactions
 patient preferences
 lifestyles habits
 other risk factors
QUESTIONS
For Dr. Mittleman and Dr. Taylor
To help us decide how to balance these factors in Ms T’s
case we asked our discussants the following questions:
1. How do you suggest assessing this patient’s risk for an
ASCVD event?
2. What do you think are the risks and benefits of starting this
patient on a statin?
3. If starting this patient on a statin, would you treat to target
or institute a moderate or high intensity statin?
OUR MODERATOR & DISCUSSANTS
• Gerald W. Smetana, MD (Moderator)
Professor of Medicine, HMS
General Medicine and Primary Care, BIDMC
• Murray A. Mittleman, MD, DrPH
Director of the Cardiovascular Epidemiology Research Unit, BIDMC
Associate Professor Medicine, HMS
Associate Professor of Epidemiology, Harvard School of Public Health
• William C. Taylor, MD
General Medicine and Primary Care, BIDMC
Associate Professor of Population Medicine, HMS
Associate Professor of Medicine, HMS
Director of Medical Education, HVMA/Atrius Health
Dr. Mittleman
Cardiology Viewpoint
QUESTIONS
How do you suggest assessing this patient’s risk for an ASCVD
event?
• AHA / ACC risk calculator is an excellent starting
point despite potential calibration issues
-Risk calculator estimates average expected risk
-Does not take all known risk factors into account
-Family history
-Lifestyle (diet, exercise, overweight)
-Measureable biomarkers / Imaging studies
-Non-cardiovascular comorbities
Although the AHA / ACC risk calculator appears to be
well calibrated in some populations, it has been
shown to overestimate risk in several cohorts:
*Reprinted from The Lancet, Volume 382, Ridker PM, Cook NR, Statins: new American
guidelines for prevention of cardiovascular disease, pp. 1762-5, Copyright © 2013, with
permission from Elsevier.
Age is the strongest risk factor
Year
Age
LDL
2009
2012
2015
61
64
67
203 mg/dL
181 mg/dL
166 mg/dL
10-year
ASCVD Risk
7.4
8.9
11.2
http://tools.cardiosource.org/ASCVD-Risk-Estimator/
*From the New England Journal of Medicine, Stampfer MJ, Hu FB, Manson JE, Rimm EB, Willett WC, Primary prevention of coronary heart disease in
women through diet and lifestyle, Vol. 343, pp. 16-22. © 2000 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical
Society.
http://www.reynoldsriskscore.org/default.aspx
RCT evidence of statin effectiveness in primary
prevention in women
*Reproduced with permission from Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary
prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results
from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and metaanalysis of women from primary prevention trials. Circulation. 2010;121:1069-77.
Number needed to treat can be estimated for
patients like Ms T.
10-year
Baseline
Risk
11.2%
8.6%*
Relative Risk
Reduction
20%
20%
10-year
Risk on
Treatment
9.0%
6.9%
Number
Needed to
Treat
45
59
*Based on the estimate that the AHA/ACC calculator may have overestimated the
10-year risk by 30%.
This compares favorably with thiazide treatment
for moderate hypertension.
*Cook NR, Ridker PM. Further insight into the cardiovascular risk calculator: the roles of statins, revascularizations, and
underascertainment in the Women's Health Study. JAMA Intern Med. 2014;174:1964-71.
More generally, the number needed to treat to
prevent one ASCVD event can be estimated:
10-year
Baseline
Risk
1%
5%
7.5%
15%
20%
Relative Risk
Reduction
20%
20%
20%
20%
20%
10-year
Risk on
Treatment
0.8%
4.0%
6.0%
12%
16%
Number
Needed to
Treat
500
100
67
33
25
• More common risks include
-Diabetes (1/1,000 patients per year)
- Monitor according to diabetes screening guidelines
-Muscle symptoms; Hepatotoxicity
- Monitor for symptoms
- Baseline ALT and CK, but no routine monitoring
• No evidence of increased cancer risk in trials,
nor in Cochrane meta-analysis of the high
quality observational studies
*Macedo AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D,
Ebrahim S. Unintended effects of statins from
observational studies in the general population: systematic
review and meta-analysis. BMC Med. 2014;12:51.
*Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J,
Blackwell L, Keech A, Simes J, et al. The effects of lowering LDL cholesterol with
statin therapy in people at low risk of vascular disease: meta-analysis of
individual data from 27 randomised trials. Lancet. 2012;380:581-90.
• Some patients require closer monitoring
-Multiple/severe comorbidities
-Impaired kidney or liver function
-Muscle disorders
-Previous statin intolerance
-Complex lipid disorders requiring multiple drugs
-Potential drug interactions
-Hemorrhagic stroke
-Age over 75 years
QUESTIONS
If starting this patient on a statin, would you treat to target or
institute a moderate or high intensity statin?
• Counsel on diet, exercise and other lifestyle
• Baseline history, physical examination, ALT & CK
• Begin moderate intensity statin
-At least one follow-up LDL
-No need to monitor regularly unless unexpected
extreme drop in LDL or clinical picture changes
• Patients with complex lipid disorders require
additional drugs and lipid panel monitoring
• Why moderate intensity statin therapy:
- The RCTs that support the use of statins in primary
prevention were designed to test standard dosing
- There is evidence that in practice, once started,
statins are rarely dose-titrated
• Research is needed to test alternative dosing
regimens to determine optimal therapy for high
value care; minimize risk and maximize benefit
and control cost
Dr. Taylor
Primary Care Viewpoint
Ground Rules:
2013 ACC-AHA Guideline*
Rationale
Evidence
QUESTIONS
1. Ms T’s Risk of ASCVD?
2. Statin Risks/Benefits?
3. Treat How?
Ms T’s Risk in 10 Years:
Pooled Cohort
Equation*
(ASCVD)
Framingham
Risk Score
(CAD)
Reynolds Risk
Score
(ASCVD)
11%
4%
2-4%
What ’s Wrong with 10-Years for
ASCVD Risk*:
1. 10 Years Arbitrary – Not Evidence-Based
2. Composite – Lumps Outcomes
3. Most Calculated Risk in Years 6-10
A. Most Subject to Calibration Bias
B. Most Affected by Discounting
4. Leads to Problems in Benefit Calculation
Questions re Ms T:
1. Risk of ASCVD?
2. Statin Risks/Benefits?
3. (Treat How?)
Reprinted with permission https://circ.ahajournals.org/content/129/25_suppl_2/S1/suppl/DC1 © 2013
American Heart Association, Inc.
Benefit Calculation Problems
Women:
“For primary prevention, fewer women
than men were enrolled in RCTs, and most
individual trials were underpowered to
test the efficacy of statin therapy on major
events in women.”*
*Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce
atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. Circulation. 2014;129:S1-45.
Benefit Calculation Problems:
What is the Evidence that Statins Reduce
ASCVD Events by 25% in Women?
Benefit Calculation Problems:
Evidence for relative risk reduction of 25% by
moderate-dose statin for men and women
without CVD with LDL-C < 190 mg/dL based on
2 studies:
• AFCAPS/TexCAPS
• MEGA
Neither showed significant benefit for women.*
*Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to
reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-45.
Benefit Calculation Problems:
“No trials were designed to determine
differential treatment effects between
men and women.”
*Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-45.
Benefit Calculation Problems:
• What about NHLBI’s ALLHAT-LLT Trial?
• Primary Prevention Trial
• Pravastatin 40mg Powered for
– Total Mortality, CHD -- Men, Women,
Minorities with Hypertension
– LDL-C 120-190 mg/dL
*The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major Outcomes in Moderately
Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual CareThe Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998.
Benefit Calculation Problems:
•
•
•
•
•
5304 Men, 5051 Women
4.8 Years (30% Crossover)
Pravastatin → LDL-C reduced 17%
No Significant Benefits in CHD or Total Mortality
Women: CHD RR 1.02 (95% Cl 0.81-1.28)
*The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major Outcomes in Moderately
Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual CareThe Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998.
Benefit Calculation Problems:
NNT = 40 for 10 Years – By Ignoring:
1. Effectiveness Uncertain for Women
2. Calibration Problem → Risk Overestimated →
Benefit Overestimated
3. Most Calculated Benefit in Later Years → Benefit
More Overestimated
4. NNT Misleading Measure at 10 Years
5. Ignores ALLHAT-LLT
What About Risk with Statins?:
Treat when NNT >> NNH*
Treat when NNT >> NNH is flawed:
1. NNT depends on time interval
2. Apples and Oranges Problem
3. Fails to Incorporate Uncertainty re Late
Risks
*Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to
reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-45.
Benefits/Risks of Statins for Ms T?:
• Respected Experts Recommend Statin, Many
MDs Agree
• Evidence for Women is Limited
• Chance of Benefit in Next Year
• <<1/100, possibly ~1-2/1,000
• Risks Seem Small, May Not Be Zero
• Might Consider Waiting for More/Better
Evidence
DR GERALD SMETANA
Who actually wrote these guidelines? Were
they written by cardiologists, primary care
doctors, by epidemiologists? I wonder if that
would have changed the outcome of the
guideline.
DR THOMAS DELBANCO
I think is far more important for her to have
a good blood pressure than a lower
cholesterol, and my suspicion is that if you
throw another pill at her and it is a statin,
there is a good chance she will take neither
of them as much as she is now, which I am
not sure she is taking. What do you think?
DR GORDON STREWLER
We haven’t heard much about her HDL.
How does that enter your thinking?
DR CAROL BATES
My anecdotal experience is that the muscle
side effects are dose-related. If exercise is
important and people stop exercising
because their muscles ache, it seems to me
very troubling to jump to 40 to 80 milligrams
of atorvastatin.
DR ANTHONY HOLLENBERG
How about a biologic plausibility with recent
genetic studies that correlate mutations that
influence LDL levels with cardiac risk in
terms of influencing whether you treat
somebody with a high level of LDL.
DR BRADLEY CROTTY
She has made great efforts in exercise and
diet and this is sort of curious. How much is
good enough? At what point do you, if you
are going to do that, say, okay enough is
enough, let’s make a decision?
EDITOR’S SUMMARY
Ms T
“I would have to look into medication before
taking it, naturally, but I would be willing to
take it. I would think about what my risk
would be if medication were prescribed and
what effect it would have on me if any.”
EDITOR’S SUMMARY
Assessing risk for ASCVD event – Pooled Cohort Equation
 Average expected risk - does not consider all risk
factors
 May overestimate risk by 30 - 50%
 NNT to prevent one ASCVD event if risk is 11.2% is 45
 NNT to prevent one ASCVD event if risk is 8.6% is 59
 Most ASCVD events are likely to occur in later years
 Composite of all ASCVD events which may be valued
differently
EDITOR’S SUMMARY
Risks and Benefits of Statin
 Primary Benefit is reducing risk of ASCVD event
 benefit may not apply equally to men and women
 benefit gained now or in the future
 Risks
 increased risk of DM
 myopathy
 hepatoxicity
 hemorrhagic stroke
 greater risk in those over 75 years of age
 Balance number needed to treat > number needed to harm
EDITOR’S SUMMARY
Treat to Target or Fixed Dose
Fixed dose
 avoids overtreatment
 avoids use of non-statin therapies which
have no proven benefit
 ? adequate data to support this approach
EDITOR’S SUMMARY
High Value Care Considerations and Further Research
 High Value Care
 Pooled cohort equation may overestimate risk leading to over
treatment
 Including the risk calculator in EMRs may increase its use
 Insurance companies removing LDL as a metric could increase use
of fixed dose treatment
 Further Research
 More accurate risk prediction tools
 Evaluate use of statins in those > 75 years
 Evaluate use of non-statin therapy for ASCVD risk reduction
 Evaluate submaximal statin dose combined with non-statin
therapies
We would like to thank…
Our Patient
Discussants
Murray Mittleman, MD, DrPH
William Taylor, MD
Beyond the Guidelines Editors
Risa Burns, MD, MPH
Deborah Cotton, MD, MPH
Eileen Reynolds, MD
Gerald Smetana, MD
Video Production
Last Minute Productions
We would like to thank…
BIDMC Media Services
Series Coordinator
Lizzie Williamson
© 2015 American College of Physicians
The information contained herein should never be
used as a substitute for clinical judgment.