Transcript Diagnosis, Prevention and Management of Statin Adverse Effects

Diagnosis, Prevention and Management of
Statin Adverse Effects and Intolerance:
Canadian Consensus
Working Group Update (2016)
G.B. John Mancini, MD, Steven Baker, MD, Jean Bergeron, MD, David Fitchett, MD,
Jiri Frohlich, MD, Jacques Genest, MD, Milan Gupta, MD, Robert A. Hegele, MD,
Dominic Ng, MD, Glen J. Pearson, PharmD, Janet Pope, MD, A. Yashar Tashakkor, MD
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Background
• The Canadian Consensus Working Group (CCWG) has published consensus
statements in 2011 and 2013 regarding statin-associated adverse effects and
intolerance.
• The Cardiovascular Imaging Research Core Laboratory (CIRCL), University of
British Columbia maintained an updated library of relevant citations from the
time of the 2013 publication to December 2015, this 2016 update is based on the
latter reference base.
• Authors were assigned sections, created summaries and representative slides,
presented to each other at a single face-to-face meeting and then reviewed,
critiqued and finalized a collated document for peer review and publication (CJC
2016).
• Logistical support for the meeting was provided by Bridge Medical
Communications, Ontario Canada through a contract with AMGEN, Canada.
• Content, interpretations and recommendations were created solely and
independently by the CCWG.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
CCWG Participants
Steven Baker, MD
Robert A. Hegele, MD
McMaster University,
Hamilton, ON
Schulich School of Medicine,
London, ON
Jean Bergeron, MD
G. B. John Mancini, MD
Laval University,
Quebec City, QC
University of British Columbia,
Vancouver, BC
David Fitchett, MD
Dominic Ng, MD
University of Toronto,
Toronto, ON
University of Toronto,
Toronto, ON
Jiri Frohlich, MD
Glen J. Pearson, MD
University of British Columbia,
Vancouver, BC
University of Alberta,
Edmonton, AB
Jacques Genest, MD
Janet Pope, MD
McGill University,
Montreal, QC
Schulich School of Medicine,
London, ON
Milan Gupta, MD
A. Yashar Tashakkor, MD
McMaster University,
Hamilton, ON
University of British Columbia,
Vancouver, BC
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Introduction
• There is continued, intense academic and social media interest in statins,
particularly adverse effects
• There is also emergence of data supporting CV event reductions with statin +
non-statin medication
• Emergence of data supporting CV event reductions are largely determined by
sustained maintenance of a physiologic state characterized by low LDL-C
• Novel, non-statin agents, including biologics, are now available
• THESE FACTS ARE PARTICULARLY GERMANE IN THE STATIN
INTOLERANT PATIENT WHOSE OSTENSIBLE SIDE EFFECTS REDUCE
QUALITY OF LIFE, DETER ADHERENCE AND LIMIT THERAPEUTIC
BENEFIT OF LDL-C LOWERING
• Pragmatic approaches to dealing with statin intolerance are needed.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Clinical Experience vs Randomized Clinical Trials:
The Elephant in the Room regarding Goal-Inhibiting Statin
Intolerance (GISI)
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
GOAL-INHIBITING CONCEPT:
Intolerance vs Resistance
• Goal-inhibiting Statin Intolerance (GISI)
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−
A clinical syndrome
Characterized by significant symptoms and/or biomarker abnormalities that
Prevent long term, indicated use of and adherence to statins as
Documented by challenge/de-challenge/re-challenge, when appropriate, using
statins, including atorvastatin and rosuvastatin, that is
− Not due to drug-drug interactions or untreated risk factors for intolerance (e.g.
hypothyroidism), and leading to
− Failure to maintain therapeutic goals as defined by national guidelines
• Goal-inhibiting Statin Resistance (GISR) is present in patients who adhere
to but do not achieve expected or adequate lipid lowering with tolerated
and maximal doses of statins.
• Both groups may require combinations of lipid lowering drugs but side
effects may be perceived differently.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Principles of Management of GISI
• Is there an indication for statin therapy?
• Does the patient have features limiting or precluding use of statins?
• Is the patient fully aware of the indication for statin treatment, intended
benefits and safety of statins, and properly counselled to avoid nocebo
effects*?
• Have dietary, weight and exercise goals been included in the therapeutic
plan? Have supplements used to avoid myalgia while taking statins been
discouraged?
• Has systematic challenge/de-challenge/re-challenge occurred and failed
to result in achievement of therapeutic goal?
• If needed, which non-statin agent is likely to help achieve therapeutic goal
with or without dual therapy to avoid polypharmacy?
*Nocebo effects; perceived adverse reactions experienced by a patient who receives a placebo.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statin Reluctance
• An attitudinal state characterized by a reluctance to use statins (“I hear
that statins are bad, right?”)
• Often unwilling to accept other forms of prescription drug therapies (“I
don’t like pills.”) but accepting of “natural” or “naturopathic” remedies and
“health supplements”
• In spite of severity of dyslipidemia, level of CV risk and appropriate
medical counselling, often feels that the problem can be addressed
entirely through dieting, specific foods or exercise programs
• Highly susceptible to nocebo effects induced by media, internet sources,
extensive “guidance” lists of side effects including those given at the
time of prescription dispensation.
• May not be amenable to establishment of true Goal-inhibiting Statin
Intolerance (GISI) or true Goal-inhibiting Statin Resistance (GISR)
Importance of National Dyslipidemia Treatment
Guidelines when Approaching GISI
• Adherence to evidence-based guidelines ensures that practice effort is
justifiable to patients, peers, regulators and payers
• Guidelines undergo regular updating to insure that indications, targets
and goals are current
• Adherence to national guidelines will not affect the concept and intention
of the pragmatic definitions of GISI (or GISR)
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Predisposing Factors for Statin-Associated Adverse
Effects: Endogenous Factors (1)
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Advanced age (older than 80 years)
Female sex
Asian ethnicity
Low body mass index, small body frame, frailty
History of pre-existing/unexplained muscle/joint/tendon pain
History of creatine kinase elevation
Family history of myopathy
Family history of myopathy with statin therapy
Severe renal disease
Acute/decompensated hepatic disease
Hypertension/heart failure (renal side effects mainly)
Hypothyroidism (untreated)
Diabetes mellitus
Neuromuscular Diseases
Genetic polymorphisms
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Adapted from Mancini G.B. et al. Can J Cardiol. 2013;29:1553-1568
Predisposing Factors for Statin-Associated Adverse
Effects: Endogenous Factors (2)
Neuromuscular diseases
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Acid maltase deficiency, amyotrophic lateral sclerosis,
carnitine palmitoyl transferase II deficiency,
cytoplasmic body myopathy, dermatomyositis, hyaline
inclusion myopathy, inclusion body myositis, McCardle
disease, malignant hyperthermia, mitochondrial
myopathy [MELAS: mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like
episodes], muscle phosphorylase B kinase deficiency,
myasthenia gravis, myoadenylate deaminase
deficiency, myotonic dystrophy types I and II,
necrotizing myopathy, peripheral neuropathy [lengthdependent, mononeuritis multiplex], polymyositis
[idiopathic, paraneoplastic], recurrent acute
myoglobinuria [Lipin-1 mutation], rippling muscle
disease (sporadic, autoimmune), spinobulbar
muscular atrophy
Adapted from Mancini G.B. et al. Can J Cardiol. 2013;29:1553-1568.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Genetic polymorphisms
•
Specific cytochrome P isoenzymes, SLCO1B1 gene
variants, “eyes shut” homolog [EYS] on chromosome
6, C34353T polymorphism in ABCB1, ABCG2
polymorphisms, ryanodine receptor (RYR1) gene,
brain-derived neurotrophic factor [BDNF] Val66Met
variant, Lipin-1 [LIPIN1] mutation, rs9806699 variant
in glycine amidinotransferase [GATM]
Predisposing Factors for Statin-Associated Adverse
Effects: Exogenous Factors
• High statin dose
• Alcohol abuse
• Illicit drug use (cocaine,
amphetamines)
• Antipsychotics
• Fibrates (primarily gemfibrozil)
• Nicotinic acid
• Amiodarone
• Verapamil
• Warfarin
• Polypharmacy therapy
Adapted from Mancini G.B. et al. Can J Cardiol. 2013;29:1553-1568.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Cyclosporine
Macrolide antibiotics
Azole antifungals
First generation protease inhibitors
Nefazodone
Large quantities of grapefruit (> 1
quart per day), pomegranate juice (?)
• Surgery with severe metabolic
demands
• Heavy and/or unaccustomed
exercise
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Genetic Risk for Goal-inhibiting Statin Intolerance
• Both common and rare genetic variants have been studied
• Reported genes encode proteins that regulate:
− Statin pharmacokinetics (e.g. drug receptors, transporters and metabolizing
enzymes)
− Statin pharmacodynamics (e.g. muscle metabolizing enzymes)
• None consistently replicated or “ready for prime time” clinical use
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Patient Counselling: Avoid Nocebo Effects
• Immediate impact of side
effects negatively alters
perceived long-term CV risk
reduction benefit and may
often outweigh them
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
• Prepare patients for repository
of data on internet, social
media, long list of side effects
distributed by pharmacies etc
• Encourage patient to discuss
any concerns with health care
provider before jumping to any
conclusions or making any
treatment changes
Silver Bullets that Don’t Yet Hit the Target!
• Some patients attempt to try to “treat” myalgia with supplements while
taking statins but patients should be counselled that none have definitely
been proven to do so:
− Coenzyme Q10
− Vitamin D
− Red yeast rice (N.B unregulated lovastatin-like drug in the rice fungus)
− Berberol (plant extract)
− Glucosamine
IDENTIFY ALL SUPPLEMENTS USED BY THE PATIENT
AND READ THEIR LABELS CAREFULLY
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Challenge/De-challenge/Re-challenge:
A Cornerstone for Documenting GISI
• Everyone has the potential to develop toxicity at a high enough dose of
statins but currently available dosage maximums have been shown to
be extremely safe
• The terms “complete” and “partial” intolerance refer to approved
dosages
• “Complete intolerance”: inability to tolerate any statin
• “Partial intolerance”: ability to tolerate a statin at some dose
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Getting to Goal Pragmatically
• Atorvastatin and rosuvastatin are the most potent statins
• They are both available in a broad dosage range
• They are both more useful than other statins in alternate day or
intermittent dosing strategies due to longer half life
• They are most likely to achieve goal and so their failure to do so
IS A STRONG INDICATION FOR ADDING ANOTHER AGENT to either:
− the maximally tolerated dose and dosing frequency of either atorvastatin or
rosuvastatin
OR
− the maximally tolerated dose of less potent statins (e.g. fluvastatin, lovastatin,
pravastatin, simvastatin) as the main, “statin-based” component of LDL-C therapy
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
When Statins Don’t Allow Goal Attainment:
What are the Options?
Readily Available
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Ezetimibe
Resins
Niacin
(Fibrates)
Limited Access
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PCSK9 inhibitors (ASCVD, FH)
Lomitapide (HoFH)
Mipomersen* (HoFH)
LDL-C apheresis (FH, high
risk/recurrent CVE)
ASCVD; Arteriosclerotic Cardiovascular Disease. FH; Familial Hypercholesterolemia. HoFH; Homozygous Familial Hypercholesterolemia. CVE;
Cardiovascular Event.
*Currently not available in Canada
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
GISI in a NUTSHELL
START/STOP
LOWER
ADD
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Trials of Atorvastatin
10-80 mg
daily/intermittently
Trials of Rosuvastatin
5-40 mg
daily/intermittently
Partial or complete
intolerance
Partial or complete
intolerance
Trials of Rosuvastatin
5-40 mg
daily/intermittently
Trials of Atorvastatin
10-80 mg
daily/intermittently
Partial or complete intolerance to
Atorvastatin and/or Rosuvastatin*
*Other statins (Simva 40 mg, Lova 80 mg, Prava 40 mg, Fluva 80 mg) may be the only tolerated statins but due to lower
potency and ineffectiveness of intermittent dosing schedules, failure to achieve goals solely through trials of these statins would
not normally be considered adequate for establishing GISI.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Partial or complete intolerance to
Atorvastatin and/or Rosuvastatin*
LDL-C within ≤ 20% of Goal
LDL-C > 20% beyond goal
Options:
Add ezetimibe
(consider other agents based on
patient preferences or patient
characteristics)
Multiple standard agents
added sequentially
(ezetimibe, resin, niacin)
PCSK9 Inhibitor
Lomitapide if HoFH
Apheresis if available
Complex polypharmacy
*Other statins (Simva 40 mg, Lova 80 mg, Prava 40 mg, Fluva 80 mg) may be the only tolerated statins but due to lower potency and ineffectiveness
of intermittent dosing schedules, failure to achieve goals solely through trials of these statins would not normally be considered adequate for
establishing GISI.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Checklist
Documenting Efforts
to Identify Maximally
Tolerated Statin-based
Therapeutic Regimen
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Management of Symptoms of Myalgia and/or HyperCKemia
SYMPTOMS OF MUSCLE PAIN OR WEAKNESS ON STATIN?
YES
CK ≤ ULN
Statin Associated
Myalgia
NO
CK > ULN
Statin Associated Myositis
CK ≤ 10 times ULN
Mild hyperCKemia
 STOP STATIN,
resume same statin
at same dose when
asymptomatic
 STOP STATIN
 REASSESS CK and
symptoms in 6-12 weeks
or sooner if symptoms
recur
 REASSESS as per
algorithm above
CK > 10 times ULN
Moderate / Severe
hyperCKemia
CK ≤ ULN
CK > ULN
CK > 10 times ULN
Moderate / Severe
hyperCKemia
CK > 5 & ≤ 10 times ULN
Mild / Grade 2
hyperCKemia
 STOP STATIN
 ASSESS if rhabdomyolysis
has impaired renal function
(CONSIDER urine myoglobin)
 REHYDRATE as warranted
 STOP STATIN
 ASSESS if rhabdomyolysis
has impaired renal function
(CONSIDER urine myoglobin)
 REHYDRATE as warranted
 RECONSIDER predisposing
factors and TREAT or
ELIMINATE, if possible
 FOLLOW until CK ≤ ULN
and symptomatic
 RECONSIDER predisposing
factors and TREAT or
ELIMINATE, if possible
 FOLLOW until CK ≤ ULN
and asymptomatic
 RECONSIDER predisposing
factors and TREAT or
ELIMINATE, if possible
 FOLLOW until CK ≤ ULN
 RECONSIDER predisposing
factors and TREAT or
ELIMINATE, if possible
 FOLLOW until CK ≤ ULN
 RESTART statin or
use lower dose or switch
 MONITOR symptoms and
enzymes in 3-6 weeks or
sooner if symptoms recur
 CONSIDER referral to
specialist to weigh risk and
benefits of restarting statins
 CONSIDER referral to
specialist to weigh risk and
benefits of restarting statins
 RESTART statin or
use lower dose or switch
 MONITOR symptoms and
enzymes in 3-6 weeks or
sooner if symptoms recur
 STOP STATIN
CK ≤ 5 times ULN
Mild / Grade 1
hyperCKemia
 CONTINUE therapy
and increase dose if
needed
 REASSESS enzymes
in 6-12 weeks or
sooner if symptoms
occur
 REASSESS as per
algorithm above
 CONSIDER nonstatin drugs as adjuncts or replacement agents to achieve lipid targets
 CONTINUE to emphasize dietary and health behavior measures to diminish need for pharmacotherapy
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003:
 NO FURTHER
TESTING
unless
symptoms
occur or statin
increased or
switched
After de novo initiation of a statin that is associated with a patient complaint
of adverse effects, when is re-challenge/de-challenge with the same statin
inappropriate or futile?
• Patient refuses to re-try the same drug, even at a lower daily dose or intermittently.
• Symptoms are significant, convincing, plausible and typical of statin side effects (mainly
myalgia) and have resolved completely with cessation.
• Symptoms are severe, associated with either
− objective muscle weakness, and/or associated with hyperCKemia (at least Mild, Grade 1b, > 5x
ULN*)
− significant ALT elevation (> 3x ULN)#
• Offending statin can be documented to be ineffective at achieving goal (note: this does
not exclude trial of this particular statin in the future or use of this agent at lower doses as
chronic therapy).
• Symptoms have not resolved or increase after a reasonable drug holiday raising the
possibility of an underlying, non-statin related illness that needs investigation prior to
addressing use of any statin or, rarely, immune mediated necrotizing myopathy possibly
statin-related.
*Note that CK elevation should be considered in the context of baseline values if known, as well as ethnicity and athletic body habitus
# Exclude trauma- or exercise-induced hyperCKemia, drug-drug interactions or concomitant use of hepatotoxic drugs, etc.)
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Ezetimibe: Logical Next Choice in GISI within 20%
of Goal
• Associated with CV risk reduction in combination with statin (SHARP,
IMPROVE-IT)
• Paucity of side effects
• Well documented safety
• Muscle-related side effect reports have been rare and not necessarily
causal (no known mechanism):
− Myopathy (Simard C, Poirier P. Can J Cardiol. 2006;22:141-144; Brahmachari B,
Chatterjee S. Indian J Pharmacol. 2015;47:563-564)
− Polymyositis (Garcia-Valladares I, Espinoza, L.R. J Rheumatol. 2010;37:472)
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
PCSK9 Inhibitors: Logical Next Choice in GISI When
LDL-C Goal is Beyond 20%
• Safe
• Effective
• Few intrinsic side effects
• Specifically studied in the GISI population
• But, access may be limited by price, indications, variability of coverage
by insurers and provincial formularies
• Definitive RCT’s pending
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Goal Achievement after Utilizing an AntiPCSK9 Antibody in Statin-Intolerant
Subjects (GAUSS): Results from a
Randomized, Double-blind, Placebo and
Ezetimibe Controlled Study
David Sullivan, MD, Anders G. Olsson, MD, Rob Scott, MD,
Jae B. Kim, MD, Allen Xue, MD, Thomas Liu, MD, Scott M. Wasserman, MD,
Evan A. Stein, MD
Sullivan D, et al. JAMA. 2012;308(23):2497-2506.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Baseline Criteria: JAMA. 2012;308:2497-2506
Characteristics
280 mg
N=32
350 mg
N=31
420 mg
N=32
AMG 145
420 mg Q4W
+ Ezetimibe
10 mg
N=30
Sex, female, n(%)
18 (56)
21 (68)
20 (63)
23 (77)
18 (56)
Age, years, mean (SD)
62 (10)
62 (9)
60 (9)
62 (7)
62 (7)
5.04 (1.25)
4.91 (1.25)
5.28 (1.56)
5.02 (1.56)
4.73 (0.94)
Free PCSK9, ng/mL, mean (SD)
383 (98)
396 (129)
372 (87)
379 (111)
390 (91)
NCEP high-risk, n (%)
14 (44)
12 (39)
11 (34)
10 (33)
15 (47)
3 (9)
5 (16)
3 (9)
6 (20)
10 (31)
≥ 1, n (%)
32 (100)
31 (100)
32 (100)
30 (100)
32 (100)
≥ 2, n (%)
28 (53)
24 (77)
23 (72)
21 (70)
25 (78)
≥ 3, n (%)
11 (34)
12 (38)
12 (38)
6 (20)
11 (34)
Myalgia, n (%)
31 (97)
29 (91)
29 (91)
29 (97)
29 (91)
Myositis, n (%)
3 (9)
3 (10)
2 (6)
2 (7)
4 (13)
AMG 145 Q4W
LDL-C, mmol/L, mean (SD)
Coronary artery disease, n (%)
Placebo Q4W
+ Ezetimibe
N=32
Statins failed (muscle-related events)
Worst statin-related events, any statin
Adapted from Sullivan D, et al. JAMA. 2012;308(23):2497-2506.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
GAUSS: Safety and Tolerability: JAMA. 2012;308:2497-2506
Adverse Events, Patient
Incidence, N (%)
280 mg
N=32
350 mg
N=31
420 mg
N=32
AMG 145
420 mg Q4W
+ Ezetimibe
10 mg
N=30
Treatment-emergent AEs
22 (68.8)
15 (48.4)
18 (56.3)
20 (66.7)
19 (59.4)
Serious AEs*
2 (6.3)
1 (3.2)
1 (3.1)
0 (0.0)
0 (0.0)
Deaths
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Treatment-related AEs
8 (25.0)
3 (9.7)
6 (18.8)
5 (16.7)
7 (21.9)
Myalgia
5 (15.6)
1 (3.2)
1 (3.1)
6 (20.0)
1 (3.1)
Muscle Fatigue
2 (6.3)
0 (0.0)
0 (0.0)
0 (0.0)
1 (3.1)
Muscle Spasms
1 (3.1)
2 (6.5)
0 (0.0)
0 (0.0)
3 (9.4)
0 (0.0)
1 (3.2)
1 (3.1)
1 (3.3)
2 (6.3)
Nasopharyngitis
2 (6.3)
2 (6.5)
1 (3.1)
3 (10.0)
5 (15.6)
Nausea
2 (6.3)
1 (3.2)
1 (3.1)
0 (0.0)
1 (3.1)
Fatigue
4 (12.5)
0 (0.0)
0 (0.0)
0 (0.0)
2 (6.3)
AMG 145 Q4W
Placebo Q4W +
Ezetimibe
N=32
Muscle-related AEs
AEs leading to discontinuation
Other most commonly reported AEs
*Four serious adverse events were reported for AMG 145: acute pancreatitis, pancreatitis, coronary artery disease, hip fracture, and syncope. None
were considered treatment related.
AE: Adverse event, some patients experienced more than 1 AE.
Adapted from Sullivan D, et al. JAMA. 2012;308(23):2497-2506.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
ODYSSEY ALTERNATIVE:
Efficacy and safety of alirocumab versus
ezetimibe, in patients with statin
intolerance defined by placebo run-in and
statin rechallenge arm
Patrick M Moriarty, MD, Paul D. Thompson, MD, Christopher P. Cannon, MD,
John R. Guyton, MD, Jean Bergeron, MD, Franklin J. Zieve, MD, Eric Bruckert, MD
Terry A. Jacobson, MD, Marie T. Baccara-Dinet, MD, Jain Zhao, MD, Yunling Du, MD,
Ronert Pordy, MD, Daniel Gipe, MD
Moriarty P, et al. J Clin Lipidology. 2016;9(6):758-769.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
ALTERNATIVE: Alirocumab Maintained
LDL-C Reductions Week 4-23
Achieved calculated LDL-C over time – on-treatment analysis
(modified ITT- Observed data only)
LDL-C, mean (SE), mmol/L
6
Alirocumab
Ezetimibe
5
4.0 mmol/L
4.1 mmol/L
4
1.5 mmol/L
3
1.7 mmol/L
2.58 mmol/L
2.5 mmol/L
2
1
2.4 mmol/L
49.5% received
150 mg Q2W at W12
0
0
4
8
12
Week
Adapted from Moriarty P, et al. J Clin Lipidology. 2016;9(6):758-769.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
16
20
24
ALTERNATIVE: Safety Analysis
Safety analysis from double-blind treatment period
Alirocumab
(N-126)
Ezetimibe (N=124)
Atorvastatin
(N=63)
TEAEs†
82.5%
80.6%
85.7%
Treatment-emergent SAEs
9.5%
8.1%
11.1%
0
0
0
TEAEs leading to discontinuation
18.3%
25.0%
25.4%
Any skeletal-muscle related TEAE‡
32.5%
41.1%
46.0%
HR (95% CI) alirocumab vs
comparator
-
0.71
(95% CI: 0.47 to 1.06)
0.61
(95% CI: 0.38 to 0.99)
P-value vs alirocumab*
-
0.096
0.042
15.9%
20.2%
22.2%
HR (95% CI) alirocumab vs
comparator
-
0.78
(95% CI: 0.43 to 1.41)
0.67
(95% CI: 0.34 to 1.32)
P-value vs alirocumab*
-
0.409
0.240
% of patients
TEAES leading to death
Skeletal-muscle related TEAE leading
to discontinuation
†TEAE
(treatment emergent adverse event) period = time from first to last injection of study treatment + 70 days.
SAE = serious adverse event.
‡Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.
*Although not pre-planned analysis, the P-value is shown for descriptive purposes.
Adapted from Moriarty P, et al. J Clin Lipidology. 2016;9(6):758-769.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
ALTERNATIVE: Fewer Skeletal Muscle AEs with
Alirocumab than with Atorvastatin
Kaplan-Meier estimates for time to first skeletal muscle event†
0.50
Atorvastatin
Cumulative probability of event
0.45
Ezetimibe
Alirocumab
0.40
0.35
0.30
0.25
0.20
0.15
Cox model analysis:
HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042
HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P=0.096
0.10
0.05
0.00
0
4
8
12
†Pre-define
16
Week
20
24
28
category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue.
ALI, alirocumab; ATV, atorvastatin; EZE, ezetimibe.
Adapted from Moriarty P, et al. J Clin Lipidology. 2016;9(6):758-769.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
32
36
Conclusions and Summary
• Adhere to the Principles of Management of Goal-inhibiting Statin
Intolerance
• Educate patients regarding the “elephant in the room” phenomenon:
although many are considered to have GISI, few are verified i.e. the
prognosis for symptomatic patients is very good
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Summary: Principles of Management of GISI
• Is there an indication for statin therapy?
• Does the patient have features limiting or precluding use of statins?
• Is the patient fully aware of the indication for statin treatment, intended
benefits and safety of statins, and properly counselled to avoid nocebo
effects?
• Have dietary, weight and exercise goals been included in the therapeutic
plan? Have supplements used to avoid myalgia while taking statins been
discouraged?
• Has systematic challenge/de-challenge/re-challenge occurred and failed
to result in achievement of therapeutic goal?
• If needed, which non-statin agent is likely to help achieve therapeutic goal
with or without dual therapy to avoid polypharmacy?
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Clinical Experience vs Randomized Clinical Trials:
The Elephant in the Room regarding Goal-Inhibiting Statin
Intolerance (GISI)
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Supplementary Slides
Challenging Scenarios and Issues
For the Generalist:
•
•
•
•
•
•
•
•
•
•
Starting off on the Wrong Foot
Drug-drug Interactions
Athletes and Laborers
Patients with Liver Disease
Patients with Renal Disease
Patients with Rheumatic and Autoimmune
Diseases
The Elderly
Intracerebral Hemorrhage
Pregnancy and Breast Feeding
Children and Adolescents
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
For the Specialist:
• Muscle Complaints and Myopathy
− Immune-mediated necrotizing myopathy
•
•
•
•
•
•
•
•
•
Cognitive Dysfunction
Glycemic Control and New Onset Diabetes
Gastrointestinal Effects
Thyroid Effects
Urogenital Health
Sexual Health
Cataracts
Dermatologic Issues
Interstitial Lung Disease
Starting Off on the Wrong Foot
• Judicious use of baseline and follow-up testing can ensure confidence in
patient-physician relationship and avoid nocebo effects
• Ensure patient understands rationale for therapy and CV benefits
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Blood Testing at Time of Initial Statin Prescription:
Baseline (to ensure proper risk assessment, identification of secondary causes of dyslipidemia and to provide
comparative values in the event of muscle or liver related complaints during follow-up):
• Lipid profile (may be non-fasting but a fasting value
should be obtained if an initial, non-fasting profile
shows abnormalities of triglycerides)
• Fasting glucose (may be reflective of pre-diabetic
state or Metabolic Syndrome) or Hemoglobin A1c (may
be non-fasting)
• Estimated GFR
•
•
•
•
•
•
Urinary Albumin/Creatinine Ratio
CK
ALT*
AST
TSH
Electrocardiogram
First Follow-up after Initiation of Statin, Switch to a Higher Dose, or Switch to a Different Statin:
• Lipid profile
• ALT
• AST
• CK
• eGFR
• HbA1c
If patient has symptoms ascribed to statin and feels the need to stop, ensure that follow-up blood testing at the time of symptoms and
cessation is performed to assist in discussing side effects and to determine if cholesterol goals were met or not.
*If cholestasis is suspected, consider alkaline phosphatase
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Scheme of Drug Metabolizing Enzymes and
Transporters involved in Statin Disposition
LUMEN
STATIN ACID OR LACTONE FORM
PASSIVE
DIFFUSION
INTESTINE
MDP 1
(P-CP)
MRP 2
ABCC2
BCRP
ABCG2
ABCB1
LACTONE
CYP3A4
KIDNEY
METABOLITE
STATIN
ACID
LUMEN
ENTEROCYTE
BLOOD STREAM
Tubular
Secretion
OAT3
STATIN ACID
LACTONE
SEC2248
STATIN
Na+
LIVER
NTCP
SEC104F
RSEP
ABCB11
BILE
HRP 2
ABCC1
OATP1B1
OATP1B1
SLCO1B1
SLCO1B1
OATP1B1
LACTONE
MDR 1
(PGP)
A9CB1
CYP3A/2C9
BILE
METABOLITE
STATIN
ACID
HEPATOCYTE
Adapted from Chauvin B, et al. Clin Phamacokinet. 2013;52(10);815-831.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003:
PROXIMAL TUBULAR CELL
SLCO1B1
BCRP
ABCG2
URINE
Clinically Significant Drug Interactions with Statins
and Dosing Recommendations (1)
Interacting Medication
Precaution/Contraindication
Amiodarone
Azole antifungals (itraconazole,
ketoconazole, posaconazole,
fluconazole, voriconazole)
Macrolide antibiotics
(erythromycin, clarithromycin,
telithromycin)
Do Not Exceed
• Simvastatin 20 mg, Lovastatin 40 mg
• CI with simvastatin, lovastatin
• CI with simvastatin, lovastatin
Amlodipine
• Atorvastatin 20 mg (with
itraconazole); Fluvastatin 20 mg twice
daily (with fluconazole)
• Atorvastatin 20 mg (with
clarithromycin); Pravastatin 40 mg
(with clarithromycin); Pitavastatin
1 mg* (with erythromycin)
• Simvastatin 20 mg
Boceprevir
• CI with simvastatin, lovastatin
• Atorvastatin 40 mg
Colchicine
• Caution with lovastatin, simvastatin,
fluvastatin, pitavastatin, pravastatin
Cyclosporine
• CI with simvastatin, pitavastatin; avoid
with lovastatin, atorvastatin
• Pravastatin 20 mg
• Rosuvastatin 5 mg
• Fluvastatin 20 mg twice daily
Danazol
• CI with simvastatin
• Lovastatin 20 mg
Digoxin
• Monitor for potential digoxin toxicity
with simvastatin and atorvastatin
*Not available in Canada
Finks SW, Campbell JD. Nurse Pract. Vol 39. 2014:45-51. Kellick, K. A., Bottorff, M., & Toth, P. P. J Clin Lipidol. 2014:8(3 Suppl):S30-46.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Clinically Significant Drug Interactions with Statins
and Dosing Recommendations (2)
Interacting Medication
Precaution/Contraindication
Do Not Exceed
Diltiazem
• Simvastatin 10 mg; Lovastatin 20 mg
Dronedarone
• Simvastatin 10 mg; Lovastatin 20 mg
Gemfibrozil
• CI with simvastatin, avoid with
lovastatin, pravastatin, pitavastatin,
atorvastatin, fluvastatin
Other Fibrates
• Caution with all statins
Grapefruit Juice (large quantities)
• Avoid with simvastatin, lovastatin
and atorvastatin
Niacin
• Caution ≥1 g/d with simvastatin,
lovastatin, rosuvastatin
Nefazadone
• CI with simvastatin and Lovastatin
Protease inhibitors
• CI with simvastatin and lovastatin
• Reduce doses of rosuvastatin
• Avoid tipranavir and ritonavir with
atorvastatin
• Rosuvastatin 10 mg (use only if needed,
avoidance recommended)
• Atorvastatin 20 mg with saquinavir +
ritonavir, darunavir + ritonavir,
fosamprenavir, fosamprenavir +
ritonavir.
• Rosuvastatin 10 mg with lopinavir +
ritonavir or atazanavir + ritonavir
• Atorvastatin 40 mg with nelfinavir
Finks SW, Campbell JD. Nurse Pract. Vol 39. 2014:45-51. Kellick, K. A., Bottorff, M., & Toth, P. P. J Clin Lipidol. 2014:8(3 Suppl):S30-46.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Clinically Significant Drug Interactions with Statins
and Dosing Recommendations (3)
Interacting Medication
Precaution/Contraindication
Do Not Exceed
Ranolazine
• Consider dose adjustment with
• lovastatin
• Simvastatin 20 mg
Rifampin
• Co-administer at same time with
atorvastatin
• Pitavastatin 2 mg*
Simepravir
• Caution with simvastatin, lovastatin,
atorvastatin, rosuvastatin,
pravastatin, and pitavastatin
Telaprevir
• CI with simvastatin, lovastatin, and
atorvastatin
Tipranavir
• CI with atorvastatin
Verapamil
• Simvastatin 10 mg; Lovastatin
20 mg
*Not available in Canada
Finks SW, Campbell JD. Nurse Pract. Vol 39. 2014:45-51. Kellick, K. A., Bottorff, M., & Toth, P. P. J Clin Lipidol. 2014:8(3 Suppl):S30-46.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Effects of Statins in Chronic Liver Diseases
Liver Disease
Statin Effects
Routine LFTs (ALT)
No longer recommended (FDA/NLA)
No new unexpected safety concerns
Drug toxicity unlikely if Bilirubin < 2X ULN
Persistent > 3X ULN (2-3 % on 80 mg/d Rx)
NAFLD/NASH
Safe. CV risk of not taking statins out-weigh risk of taking the drug.
Reduced transaminases and improved steatosis/necroinflammation in
some pilot studies. Not yet a treatment for NAFLD per se.
PBC*
To be considered in patients with additional CV risk factors. Effective in
reducing TC/LDL and safe. No PBC progression and might have a
beneficial effect on PBC itself (one study, 3 years).
Drug-induced autoimmune
hepatitis
Rare, variable in severity, likely idiosyncratic associations, but
increasingly reported. Appears safe in systemic autoimmune disease
with/without AILD
AILD; Alcohol induced liver disease *Patients may present with high total cholesterol attributable mainly to LpX, not LDL-C or apo B containing
particles; therefore apo B measurement is useful in this setting to identify atherogenic dyslipidemia possibly warranting therapy
Adapted from Herrick C, et al. Card Clin. 2015;33(2):257-265.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Effects of Statins in Chronic Liver Diseases
and GI Tract
Liver Disease
Statin Effects
Hepatitis C
Less severe liver enzyme elevations. Could improve antiviral response.
Reduced risk of cirrhosis/carcinoma.
Chronic liver disease
Compensated cirrhosis
(Child-Pugh A)
No contraindication for statins. Decrease carcinoma and may reduce CV risk.
Drug interactions to be considered in some specific diseases.
Liver transplantation
Safe with appropriate consideration for drug interactions.
Excessive ethanol intake
(> 1-2 Units/d)
May increase liver enzymes. No data for pharmacologic interactions in humans.
Nausea-Heartburn,
Constipation-Diarrhea
(bowel dysmotility)
Not seen in clinical trials and meta-analysis. Symptomatic benefit with
discontinuation (some case reports).
Cholelithiasis
GI malignancies
Decrease in cholelithiasis, esophageal and colorectal cancers by potential
pleiotropic effects in statin users.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and Suspected Liver Disease
 Absence or very low suspicion of acute or decompensated liver disease
 Transaminases ≤ 3 times ULN
 START statin
TRANSAMINASES
≤ 3 TIMES ULN
TRANSAMINASES
> 3 TIMES ULN
REASSESS in 6-12 weeks
Symptomatic
Asymptomatic
STOP STATIN
 CONSIDER other causes (eg. Alcohol)
and eliminate or TREAT if warranted
STOP STATIN
REASSESS in 6-12 weeks
or sooner if clinically warranted
TRANSAMINASES
> 3 TIMES ULN
TRANSAMINASES
≤ 3 TIMES ULN
 NO FURTHER
Transaminase testing
unless symptoms
occur or statin
increased or switched
Prior evaluation
≤ 5 times ULN
Prior evaluation
> 5 and ≤ 8 times ULN
Prior evaluation
> 8 times ULN
 RESTART same statin
at same or lower dose
or
 SWITCH statin
 RESTART same statin
at lower dose
or
 SWITCH statin
 SWITCH statin and use
low initial dosing
 CONSIDER referral
 INVESTIGATE for intrinsic
liver disease
 CONSIDER referral
 REASSESS in 3-6 weeks or sooner if clinically warranted
 CONSIDER nonstatin drugs as adjuncts or replacement agents to achieve lipid targets
 CONTINUE to emphasize dietary and health behavior measures to diminish need for pharmacotherapy
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003:
Statins and Rheumatic Conditions
• There is no absolute contraindication beyond usual contraindications
• The higher CV burden in patients with chronic inflammatory conditions
needs to be recognized
• Statins decrease CV risk in these patients
• Usually statins have other benefits (anti-inflammatory, anti-cytokine) but
rarely perturbation of the immune system can be a problem:
− Statins can give chronic inflammatory myositis associated with antibodies to
HMGCoA reductase leading to pain and necrosis which is sustained after D/Cing the
statin
• Caution should be used in those with other hepatoxins and concomitant
conditions that elevate CK or cause myalgias but this is due to
uncertainty in attribution of side effects of statin vs. the rheumatic
disease being treated
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and Intracerebral Hemorrhage
• Meta-analyses show minimal to no association:
− 32 studies involving >248,000 patients1
− 31 studies involving >193,000 patients2
− 11 studies involving >73,000 patients3
• 2o analysis of Women's Health Initiative (67,882 followed for 12 years): no
relationship of statin and hemorrhagic stroke4
• Meta-analysis of 11 observational studies of >6900 patients:
no association of ongoing statin use before ICH onset5
• Phase 3 RCT in 803 patients with aneurysmal SAH on simvastatin or
placebo was neutral after 6 months6
1. Hackam DG, et al. Circulation. 2011;124:2233-42. 2. McKinney JS, et al. Stroke. 2012; 43:2149-56. 3. Wang W, et al. PLoS One. 2014; 9:e92388.
4. Salmoirago-Blotcher E, et al. BMJ Open. 2015;5:e007075. 5. Lei C, et al . Eur J Neurol. 2014;21:192-8. 6. Kirkpatrick PJ, et al. Lancet Neurol
2014;13:666-75.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and Elderly
• Competing morbidity/mortality issues, frailty, patient/family preferences
are important factors to weigh for use or non-use of statins
• Statin meta-analyses of RCT’s suggest positive event reductions and
good tolerance except in frail elderly
• Advanced age is not a contraindication
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and Pregnancy
• Early reports of congenital abnormalities or teratogenicity in children of
women on statins have not been substantiated
• Cohort studies and meta-analysis do not identify a clear signal for harm
• Statistical power remains insufficient to challenge current
recommendations of treatment discontinuation during pregnancy
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and Lactation
• There is a lack of data concerning levels of statins in the breast milk of
mothers
• Case report indicate that breast milk concentration of statins is low
• In the absence of safety data, statins should not be used in breastfeeding mothers
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and Children
• A healthy lifestyle is the therapeutic cornerstone for all children with
HeFH
• Statin therapy in children > 10 years is safe and well tolerated
• Initiation of statins depends on additional variables, such as a high
burden of cardiovascular disease risk factors, family history and the
absolute LDL-C level
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
CCWG Terminology for Myopathic Syndromes and
HyperCKemia
Characteristics
Term
Laboratory
Clinical
Myopathy
NA
General term referring to any disease of muscle
Myalgia
CK ≤ ULN
Muscle ache/weakness
Myositis
CK > ULN
Muscle ache/weakness
Rhabdomyolysis
CK > 10 times ULN
Muscle ache/weakness; renal dysfunction might result from
myoglobulinuria; need for hydration therapy
Symptomatic myopathy
(CK > 10,000 U/L)
HyperCKemia
Mild, grade 1
CK > ULN, ≤ 5 times ULN
Might/might not have myositis
Mild, grade 2
CK > 5 times ULN, ≤ 10 times ULN
Might/might not have myositis
Moderate
CK > 10 times ULN; ≤ 50 times ULN
Severe
CK > 50 times ULN
Adapted from Mancini, et al. Can J Cardiol 2013;29:1553-1568.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Might/might not have rhabdomyolysis with/without renal
dysfunction
Might/might not have rhabdomyolysis with/without renal
dysfunction
Continuous vs. Discrete
Statin-Associated Adverse Effects
Myalgia
Myositis
VS.
Myalgia
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Myositis
Definition of Muscle Side-effects
• Rhabdomyolysis
− Significant CK elevation with weakness
− Myoglobinuria is not a requirement
• Classification of CK elevations (arbitrary)
• Mild hyperCKemia: <10x ULN (?myositis)
• Moderate hyperCKemia: 10-50x ULN
• Severe hyperCKemia: >50x ULN
• Myositis → Rhabdomyolysis is a continuum (CK < 10 ULN + weakness
vs CK 10+ x ULN + weakness are not truly distinct so degree of
hyperCKemia in the presence of neurological findings should not be
overly weighed)
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
250
120
200
100
Number of Participants
Number of Participants
Distribution of Creatine Kinase in the General
Population: Implications for Statin Therapy
150
100
50
80
60
Black
40
White
20
0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
4,0
Log CK
Distribution of log CK within the population. Log CK shows a polymodal
frequency distribution. The log of the ULN as provided by the assay
manufacturer was 2.15 in women and 2.4 in men.
Adapted from Brewster, et al. Am Heart J. 2007;154:655-661.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
0
0,5
1,0
1,5
2,0
2,5
3,0
Log CK
Distribution of log CK in white and black people
4,0
Assessment of CK elevation in relation to ethnicity
and sex
Sex
percentile of CK
Relative Reference
Value (97.5th
percentile for white
ethnicity and sex)
Female
201
201
X 1.0
> 5.0x ULN
Male
322
322
X 1.0
> 5.0x ULN
Female
313
201
X 1.6
> 8.0x ULN
Male
641
322
X 2.0
> 10.0x ULN
Female
414
201
X 2.0
> 10.0x ULN
Male
801
322
X 2.5
> 12.5x ULN
Ethnicity- and sexspecific 97.5 th
Ethnicity
White
South East
Asian
Black
Relative Upper Limit
of Normal Compared
to White Ethnicity
Mild, Grade 1b
“hyperCKemia”
threshold relative to
CK limits for white
ethnicity
Adapted from Brewster, et al. Am Heart J. 2007;154:655-661.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Causes of Asymptomatic or
Minimally Symptomatic HyperCKemia
• Endocrine disorders
−
−
−
•
•
•
•
•
•
•
Hyperthyroidism
Hypothyroidism
Hypoparathyroidism
Connective tissue disorders
Cardiac disease
Acute kidney disease
Viral illnesses
Pregnancy
Celiac disease
Medications
−
−
−
−
−
−
−
−
• Toxins
HMG-CoA reductase inhibitors (statins)
Fibrates
Anti-retrovirals
Beta-blockers
Clozapine
Angiotensin receptor blocking agents
Hydroxychloroquine
Isotretinoin
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
−
−
−
Ethanol
Cocaine
Heroin
• Metabolic disturbances
−
−
−
Hyponatremia
Hypokalemia
Hypophosphatemia
• Strenuous exercise
• Muscle trauma
−
−
−
•
•
•
•
Intramuscular injections
Needle electromyography
Seizures
Surgery
Malignancy
MacroCK
Idiopathic hyperCKemia
CCWG Modification of Statin Associated Muscle
Symptom (SAMS) Score
Clinical symptoms (new or increased unexplained muscle symptoms)
Regional distribution/pattern
• Symmetric hip flexors/thigh aches
• Symmetric calf aches
• Symmetric upper proximal aches
• Non-specific, asymmetric, intermittent
• Transient during continued statin use
Temporal Pattern
• Symptoms onset ≥ 2 days# and < 4 weeks
• Symptoms onset 4 – 12 weeks
• Symptoms onset > 12 weeks
• Symptom onset < 2# days
De-challenge*
• Improves upon withdrawal (2 days to < 2 weeks)
• Improves upon withdrawal (2 – 4 weeks)
• Does not improve upon withdrawal (> 4 weeks)
• Asymptomatic during day of first missed dose
3
2
2
1
0
3
2
1
0
Re-Challenge
• Same symptoms recur upon re-challenge ≥ 2 days and < 4 weeks
• Same symptoms recur upon re-challenge 4 – 12 weeks
• Same symptoms occur with non-statin lipid lowering drugs
3
1
0
History of Response to Non-lipid Lowering Medications
• Same symptoms as reported with statins
-5
•
Modified SAMS Score
−
−
−
Probable
Possible
Unlikely
≥9
7–8
<7
2
1
0*
0
#Intended
to distinguish between patients reacting after only one dose compared to multiple, daily doses.
*In rare cases of immune-mediated necrotizing myopathy symptoms may persist or worsen despite statin cessation. Ensure absence of hyperCKemia
or markers of inflammation if significant symptoms persist off of statin.
Adapted from Rosenson, et al, Journal of Clinical Lipidology. 2014;8:S58-71.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Immune-mediated Necrotizing Myopathy
• An autoimmune disease
• Usually assoc. w/ CK >5,000 U/L
• Proximal distribution
• No skin changes (i.e., malar rash, Gottron’s sign)
− Malar rash: butterfly rash over face and cheeks
− Gottron’s sign: rash over extensor surfaces of digits (i.e. knuckles)
− Both Malar rash and Gottron’s sign are seen in dermatomyositis
• + Anti-HMGCR Ab
• Persists or worsens despite statin withdrawal
• Can develop without statin exposure
• Bx: lack of inflammatory infiltrate, prominent necrosis
• 2 per million per year; 6% of acquired myopathy @ Johns Hopkins Myositis Center
• (Recent review: Mammen AL, NEJM 2016; 374;664-9.)
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Toxic vs Autoimmune Myopathy
A comparison of toxic statin myopathy with statin-associated autoimmune myopathy
Toxic statin myopathy
Statin-associated autoimmune myopathy
Symptoms
Myalgias common; Weakness infrequent
Myalgias common; Weakness common
Maximum creatine kinase (IU/I)
Normal (with mild disease) to > 100 000
(with rhabdomyolysis)
1000-50 000 IU/I
Muscle biopsy
Mild disease: cytochrome oxidase negative
fibres, vacuolization; sever disease:
myofiber necrosis and regeneration with
minimal inflammation
Myofiber necrosis and regeneration with minimal inflammation;
MHC class I up-regulation; MAC deposition on non-necrotic fibers
Genetic risk factors
SNP in SLCO1B1
HLA-DRB1*11:01
Anti-HMGCR antibody
Absent
Present
Clinical course after statin
discontinuation
Improvement
Persistent/progressive weakness and CK elevation
Appropriate therapy
Statin withdrawal (or dose reduction)
Statin withdrawal and immunosuppressive therapy
CK, creatine kinase; HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; MHC, major histocompatibility complex; SNP, single nucleotide
polymorphism
Adapted from Mohassel, et al. Curr Opin Rheumatol. 2013;25:747-52.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statin Exposure
Metabotoxic effect
Statin withdrawal
Non-immune
Myonecrosis
+
HyperCKemia
Resolution of
Toxicity
Statin withdrawal
Dysimmune
Propagation of
symptoms
Immunophenotype-specific response
Necrotizing
myopathy
Inflammatory
myopathy
Immunosuppression
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
HMGCR Ab seropositivity in necrotizing myopathies
(NM), established by histopathology
Necrotizing
Myopathy
(n)
HMGCR
Ab+
(n)
HMGCR
Ab+/NM
(%)
Statin
Exposed
(n)
Ab+
Exposed to
Statins
(%)
Mammen 2011
128*
45
35
30
67
0.23
Allenbach 2014
206
45
22
20
44
0.10
Kassardjian 2015
63
17
27
12
71
0.19
Watanabe 2015
26
8
31
3
38
0.12
Klein 2015
27
11
41
11
100
0.41
Totals
450
126
28
76
60
0.17
Probability of
Ab+ & Statin
Exposure
Summary of 5 studies examining the frequency of HMGCR Ab seropositivity in necrotizing myopathies (NM), established by histopathology, and the
prevalence of statin exposure. *The total number of NM cases was not disclosed in this study. It was assumed, based on previous work, ChristopherStineA&R2010 that NM represents approximately 17% of all-cause acquired myopathies ( 750 x 0.17 = 128). Ab, antibody.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Myositis-specific AutoAbs
• Top 3
− Amino-acyl tRNA synthetases
− nti-Mi2 (nuclear helicase)
− Anti-SRP (signal recognition particle)
• Novel AutoAbs
− Anti-MDA5 (CADM-140)
− Anti-MJ/NXP2 (nuclear matrix protein)
− Anti-TIF1-g (transcriptional intermediary factor 1-g)
− Anti-SAE (small ubiquitin-like modifier activating enzyme)
− Anti-HMGCR
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Syndromes in the Myositis Spectrum
These patients can present as a diagnostic challenge and/or
have an ‘overlap’ feel. They may have minimal or no muscle
involvement or similarly subtle/no cutaneous disease. They may
initially present with polyarthrititis, ILD or rash in isolation and
therefore may be assessed by a range of different specialties.
These patients are most likely to present with
severe myositis with a very high CK and
profound weakness.
Amyopathic disease
Interstitial lung disease
Anti-PmScl
Anti-aminoacyl tRNA synthetases
Necrotising myositis
Malignancy
Anti-MDAS
Anti-SAE
Anti-MI2
Anti-TIF1
Anti-NXP2
(Anti-Jo1, Anti-PL-7, Anti-EH, Anti-PL-12, Anti-KS, Anti-OJ)
Skin disease
Polyarthritis, Raynaud’s Phenomenon and Mechanic’s Hands
These patients are most likely to present with
both cutaneous and muscle disease. They
may have an associated malignancy.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003:
Anti-SRP
Anti-HMGCR
Consider a Muscle Biopsy When:
1.
Myoglobinuria*
2.
Second wind phenomenon*
3.
Weakness*
4.
Muscle hypertrophy/atrophy*
5.
Persistent increase of CK (> 2-3 above
baseline or ULN based on age, sex, ethnicity)*
6.
Myopathic EMG (fibrillations and/or +ve sharp
waves)*
7.
Other considerations:
1.
Abnormal neurologic exam
2.
CK does not normalize after statin withdrawal
3.
HyperCKemia with re-exposure to statin
4.
+ Family History
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
*European Federation of Neurological Sciences,
Kyriakides, et al. Eur J Neurol. 2013;997 -1005.
NB: 2nd wind (SOB and excessive perceived exertion
at onset of exercise that then abates) and
hypertrophy are NOT seen with statin myopathy;
atrophy is not typical of statin myopathy
Cognitive Adverse Effects
• Cognitive considerations should not play a routine role in medical
decisions regarding prescription of statins
− Decision to prescribe statins should not be altered on this basis for majority of
patients
• Baseline assessment of cognition prior to initiating statins not warranted
− Patient-reported cognitive symptoms should be thoroughly investigated and not
readily dismissed
• Statins may have a dose and duration related protective effect on certain
forms of dementia
− Larger/better-designed studies needed to draw unequivocal conclusions about the
protective effect of statins on cognition
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and New-Onset Diabetes:
Mechanisms
• Mechanism remains to be elucidated
• Murine studies → upregulation of PTEN, implicated in insulin resistance
• Direct effect of HMG CoA reductase inhibition
• Recent FH analysis reveals lower prevalence of DM compared to
unaffected relatives, with variability in DM risk by LDL-receptor mutation
type; suggesting a link between LDL-receptor mediated cholesterol
transport and DM
• Statins may therefore cause NOD by upregulating cholesterol transport
into hepatocytes and pancreatic beta cells
FH; Familial Hypercholesterolemia. NOD; New-onset of diabetes
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003
Statins and New-Onset Diabetes:
Clinical Implications
• For every case of NOD caused by statin therapy, several more hard CV
events are avoided, both in primary and secondary prevention
• General consensus that clinical benefits of statins outweigh risk of NOD
• Very long-term risk/benefit ratio remains unclear, though seems
favorable from extension studies
• Risk of NOD should generally not be a factor in withholding statin
therapy from deserving populations
Sattar N, et al. Lancet. 2010;375:735-42; Preiss D, et al. JAMA. 2011;305:2556-64; Ridker PM, et al. Lancet. 2012;380:565-71; Waters DD, et al. J
Am Coll Cardiol. 2013;61:148-52; Kohli P, et al. J Am Coll Cardiol. 2015;65:402-4; Fulcher J, et al. Lancet. 2015;385:1397-405; Erqou S, et al.
Diabetologia. 2014;57:2444-52; Birnbaum Y, et al. Cardiovasc Drugs Ther. 2014;28:447-57; Besseling J, et al. JAMA. 2015;313:1029-36; Frayling TM.
Lancet. 2015;385:310-2.
Mancini et al, DOI: http://dx.doi.org/10.1016/j.cjca.2016.01.003