Transcript Evolving Management of Vascular diseases Through the years

Evolving Management of Vascular Diseases
through the Years
Jenny L. Beltran, MD, FPCP, FPCC, FSVM
43rd PHA Annual Convention
May 23-25,2012
NO DISCLOSURE
Venous Thromboembolism
ACCP Conference on Antithrombotic & Thrombolytic
Therapy for Venous Thromboembolism
Objectively
Confirmed
DVT/PE
2004 evidencebased guidelines
(7th ed.)
2008 evidencebased guidelines
(8th ed.)
2012 evidencebased guidelines
(9th ed.)
Comments
therapy: LMWH
or IV heparin
LMWH or
monitored IV or
SQ heparin,
unmonitored IV or
SQ UFH or
fondaparinux
LMWH or
monitored IV or
SQ heparin,
unmonitored IV or
SQ UFH or
fondaparinux
2008 guidelines
remain current in
2012 guidelines
Treatment with VKA
for 6-12 months
Treatment with VKA
for 3 months
Treatment with VKA
for 3 months
2008 guidelines
remain current in
2012 guidelines
GRADE 1A
Unprovok
ed
proximal
DVT or PE
GRADE 1A
GRADE 1A
GRADE 1B
ACCP Conference on Antithrombotic &
Thrombolytic Therapy on Venous Thromboembolism
VTE
prophylaxis
In HFS,
THA, TKA
2004 evidencebased guidelines
(7th ed.)
2008 evidencebased guidelines
(8th ed.)
2012 evidencebased guidelines
(9th ed.)
Comments
No
recommendation
LMWH,
fondaparinux for
10-14 days
LMWH,
fondaparinux,
apixaban,
dabigatran,
rivaroxaban.
LDUH, adjusteddose VKA,ASA for
10-14 days
New
recommendation
on apixaban,
dabigatran,
rivaroxaban and
ASA in 2012
guidelines
GRADE 1B
THA,TKA,HFS
Decline or
uncooperative
with injections
or IPC VTE
prophylaxis
No recommen
dation
No recommendation
Apixaban or
dabigatran
(alterantively
rivaroxaban or
adjusted dose
VKA)
New
recommendation
In 2012 guidelines

Traditionally, strict bed rest for several
days in combination with IV heparin to
avoid thrombi from breaking off and
causing PE.

2 randomized studies with limited sample
sizes : bed rest plus anticoagulation was
not shown to reduce the incidence of
silent PE as detected by lung scanning
Arch Int Med 1992, Ann Int Med 1993
Year 2001 : the rate of resolution of pain
and swelling was significantly faster with
early ambulation and leg compression
VASA 2001
garments
 Cohort of 1289 patients with acute DVT
treated with LMWH: low incidence of
recurrent and fatal PE : mobile patients do
not require bed rest

J Vasc Surg 2000
Peripheral Arterial Disease
Recommendations for Antiplatelet &
Antithrombotic Drugs
2005 recommendations
CLASS 1
ASA, 75-325 mg OD
safe & effective
antiplatelet
reduce the risk of MI,
stroke or vascular death
in atherosclerotic LE
PAD (LOE : A)
2011 Focused Update
Comments
ASA, 75-325 mg OD
safe & effective
antiplatelet
reduce the risk of MI,
stroke, or vascular death
with symptomatic
atherosclerotic LE PAD,
including those with
intermittent claudication
or critical limb ischemia,
prior LE
revascularization
(endovascular or
surgical) or prior
amputation for LE
ischemia (LOE: B)
Modified
recommendation
(wording clarified : LOE
changed from A to B)
ACCF/AHA Task Force on Practice Guidelines
2011 Focused Update of the Guidelines on
the Management of PAD

Review of 5 RCTs & 1 meta-analysis

2002 Antithrombotic Trialist’s Collaboration metaanalysis:
significant reduction in CV events among
symptomatic PAD patients randomized to
antiplatelet vs placebo
 significant heterogeneity of enrollment criteria
and antiplatelet dosing regimens

ACCF/AHA Task Force on Practice Guidelines
2011 Focused Update of the Guidelines on
the Management of PAD

Review of 3 RCTs of aspirin use (100mg daily) vs placebo for
CV risk reduction among PAD patients

2 larger trials with longer duration of ff-up : no benefit of
aspirin
1) POPADAD (Prevention of Progression of Asymptomatic
Diabetic Arterial Disease) : ABI < 0.99
2) Aspirin for Asymptomatic Atherosclerosis trial
ABI < 0.95, calculated the ABI using the lower pedal
pressure
enrolled only asymptomatic patients derived from
population screening based on very mild decrements in ABI
(low risk patients)




JAMA 2010
BMJ 2008
2011 Focused Update of the Guidelines
on the Management of PAD

CLIPS (Critical Leg Ischemia Prevention Study)
enrolled patients with more advanced PAD
(symptoms and/or ABI <0.85)
 significant reduction in CV events randomized
to aspirin
 stopped early due to poor recruitment
(366/2000 patients)

2011 Focused Update of the Guidelines on
the Management of PAD
2009 meta-analysis of aspirin therapy for PAD
JAMA 2009
patients:
 CLIPS and POPADAD trials only
 34% risk reduction for nonfatal stroke
 no significant reduction in the overall CV
events


Recommended dose range of aspirin : 75mg to
325mg /day
Recommendations for Antiplatelet &
Antithrombotic Drugs
2005 Recommendations
CLASS 1
Clopidogrel, 75 mg OD
effective alternative
antiplatelet to ASA
to reduce the risk of
MI, stroke or vascular
death in atherosclerotic
LE PAD (LOE: B)
2011 Focused Update
Comments
Clopidogrel, 75 mg OD Modiified
safe & effective
recommendation
alternative to ASA to
(wording clarified)
reduce the risk of MI,
ischemic stroke, or
vascular death in
symptomatic
atherosclerotic LE PAD,
including intermittent
claudication, or critical
limb ischemia, prior LE
revascularization
(endovascular or
surgical) or prior
amputation for LE
ischemia (LOE : B)
ACCF/AHA Task Force on Practice Guidelines
2011 Focused Update of the Guidelines on
the Management of PAD
After CAPRIE ( Clopidogrel vs Aspirin in
Patients at Risk of Ischemic Events) :

no new clinical trials directly compared ASA
monotherapy with clopidogrel

CHARISMA (Clopidogrel for High
Atherothrombotic Risk and Ischemic
Stabilization, Management & Avoidance) :
 reasonable to combine ASA with clopidogrel
for certain high risk patients with PAD who are
not at increased risk of bleeding

CHARISMA (Clopidogrel for High Atherothrombotic Risk
and Ischemic Stabilization, Management & Avoidance) :






Patients with PAD in the CHARISMA trial:
Aim : to determine whether clopidogrel plus ASA provides greater
protection against major CV events than ASA alone in patients with
PAD
Inclusion criteria for PAD:
1) symptomatic PAD :either current intermittent claudication
together with ABI > 0.85 or history of intermittent claudication
together with a previous related intervention (amputation, surgical
or catheter based peripheral revascularization)
2) asymptomatic PAD : ABI of 0.9 with multiple risk factors
Prospective, randomized, multicenter, double blind, placebo
controlled : 3096 patients with symptomatic (2838) or
asymptomatic PAD
CHARISMA (Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management & Avoidance) :
Primary endpoint : first occurrence of MI, stroke (of any cause), or death
from CV causes (including hemorrhage)
 Principal secondary endpoint : first occurrence of MI, stroke, death from
CV causes, hospitalization for UA, TIA, or a revascularization procedure
(coronary, cerebral, or peripheral)










Results :
Primary endpoint: 7.6% in clopidogrel plus ASA;
8.9% in placebo plus ASA
Rate of MI : 2.3% in clopidogrel plus ASA
3.7% in placebo plus ASA
Rate of hospitalization for ischemic events : 16.5% in clopidogrel plus
ASA; 20.1% in placebo plus ASA
Severe, fatal, or moderate bleeding : did not differ between groups
Minor bleeding : 34.4% in clopidogrel plus ASA
20.8 % in placebo plus ASA
Recommendations for Antiplatelet &
Antithrombotic Drugs
2005 Recommendations
2011 Focused Update
Comments
Antiplatelet therapy
useful to reduce the
risk of MI, stroke, or
vascular death in
asymptomatic patients
with ABI < 0.9 (LOE: C)
NEW recommendation
CLASS 11a
CLASS 11b
The usefulness of
NEW recommendation
antiplatelet therapy to
reduce the risk of MI,
stroke, or vascular death
in asymptomatic
individuals with
borderline abnormal ABI,
0.91 – 0.99 is not well
established (LOE: B)
ACCF/AHA Task Force on Practice Guidelines

no clinical trials have examined the
efficacy of the new antithrombotics such
as prasugrel, and ticagrelor to reduce
ischemic events in patients with PAD
Recommendations for Critical Limb Ischemia :
Endovascular & Open Surgical Treatment for Limb
Salvage
2005 Recommendations
CLASS 1
Combined inflow &
outflow disease with
critical limb ischemia,
inflow lesions should be
addressed first (LOE: C)
Combined inflow &
outflow disease with
critical limb ischemia or
infection persist after
inflow revascularization,
outflow revascularization
should be
performed(LOE: B)
2011 Focused Update
Comments
2005 recommendation
remains current in 2011
focused update
2005 recommendation
remains current in 2011
focused update
ACCF/AHA Task Force on Practice Guidelines
Recommendations for Critical Limb Ischemia:
Endovascular & Open Surgical Treatment for Limb
Salvage
2005 Recommendations
2011 Focused Update
Comments
CLASS 11a
Limb-threatening LE
NEW recommendation
ischemia & estimated life
expectancy of < 2 years
or an autogenous vein
conduit is not available,
balloon angioplasty is
reasonable to perform
when possible as the
initial procedure to
improve the distal blood
flow (LOE:B)
ACCF/AHA Task Force on Practice Guidelines
Recommendations for Critical Limb Ischemia :
Endovascular & Open Surgical Treatment for limb
Salvage
2005 Recommendations
2011 Focused Update
comments
CLASS 11a
Limb threatening
NEW recommendation
ischemia & an estimated
life expectancy > 2 years,
bypass surgery, when
possible & when an
autogenous vein conduit
is available, is reasonable
to perform as the initial
treatment to improve
the distal blood flow
(LOE:B)
ACCF/AHA Task Force on Practice Guidelines
BASIL ( Bypass Versus Angioplasty in Severe
Ischemia of the Leg)

Funded by the UK NIH Research & Health Technology Assessment
Programme
5 year period, 452 patients with CLI (rest/night pain, & tissue
loss such as skin ulceration & gangrene)

randomized to either open surgery or balloon angioplasty

major clinical outcomes :

amputation-free survival & overall survival

Initial results in 2005, CLI with infrainguinal disease

similar short term clinical outcomes between bypass
surgery-first & balloon angioplasty first

bypass surgery-first was one third more expensive

associated with higher morbidity

BASIL (Bypass Versus Angioplasty In Severe
Ischemia of the Leg)
Mean follow-up of 3.1 yr (range :1 – 5.7 yrs)

bypass surgery-first : significant increase in overall
survival of 7.3 months (95% CI:1.2 to 13.4 months;
P= 0.02) & a trend toward improved amputation-free
survival of 5.9 months(95%CI: 0.2 to 12 months; P=0.6)
who survived for at least 2 years after randomization
BASIL (Bypass Versus Angioplasty in Severe
Ischemia of the Leg)

Reasonable for a bypass surgery first approach
to be considered for these carefully selected
patients to prolong amputation free survival &
overall survival.

Confirmed that outcomes ff prosthetic bypass
were extremely poor
PERSONALIZED
VASCULAR MEDICINE :
ARE WE READY?

Give different drugs to different
patients, for the sweet ones do
not benefit everyone, nor do the
astringent ones, nor are all the
patients able to drink the same
things.
Hippocrates, circa 400 BC

recognizing the “great natural diversities” between
persons, he instructed his students to “give different drugs to
different patients” to both maximize efficacy and minimize
adverse effects
Novel strategies designed to permit
tailoring 3 major pharmacotherapeutic
drug classes within vascular medicine:

antiplatelet therapy

lipid lowering therapy

antithrombotic therapy

Antiplatelet therapy

Residual high platelet reactivity on
antiplatelet therapy represent a significant
proportion with atherosclerotic disease,
& a markedly increased risk of future
events

Emergence of novel potent antiplatelets
and point-of-care platelet function assays
and genetic testing : genotype &
phenotype based individualized therapy
Overview of Approaches to Personalize
Pharmacotherapeutic Management in Vascular Medicine
Pharmacotherap
eutic Area
Therapeutic
Question
Guiding Tests
Potential
Personalized
intervention
Antiplatelet
therapy
Aspirin dose,
clopidogrel dose,
or need for
combination
therapy
Platelet
aggregation assays
(VerifyNow,
PRA-100)
Substantial
platelet
aggregation
suggests residual
high platelet
reactivity
Benefit from
higher dose ASA,
higher
clopidogrel,
prasugrel, or
combination
therapy including
omega 3FA or
cilostazol

Loss of function CYP2C19 alleles
CYP2C19*2 or *4 : 22% less platelet
inhibition upon exposure to clopidogrel

patients with 2 loss of function CYP2C19
alleles and HPR : less responsive to dose
escalation of clopidogrel
Overview of Approaches to Personalize
Pharmacotherapeutic Management in Vascular Medicine
Pharmacotherap
eutic Area
Antiplatelet
therapy
Therapeutic
Question
Aspirin dose,
clopidogrel dose,
or need for
combination
therapy
Guiding Tests
Potential
Personalized
intervention
Cytochrome
P450 2C19
(CYP2C19)
genotype
Carriers of
CYP2C19 variants
CYP2C19*2 or
CYP2C19*4 :
reduced
conversion of the
clopidogrel prodrug to the active
metabolite
Benefit from
higher dose
clopidogrel or the
alternative
prasugrel
Overview of Approaches to Personalize
Pharmacotherapeutic Management in Vascular Medicine
Pharmacotherap
eutic Area
Therapeutic
Question
Guiding Tests
Antiplatelet
therapy
Aspirin dose,
clopidogrel dose
or need for
combination
antiplatelet
therapy
Paraoxonase 1
Carriers of the
(PON 1) genotype PON1 allele
QQ192 : reduced
conversion of the
clopidogrel prodrug to the active
metabolite
Benefit from
higher dose
clopidogrel or the
alternative
prasugrel
Potential
Personalized
Intervention
Overview of Approaches to Personalize
Pharmacotherapeutic Management in Vascular Medicine
Pharmacotherap
eutic Area
Therapeutic
Question
Guiding Tests
Potential
Personalized
Intervention
Lipid-lowering
therapy
Statin drug or
dose
Solute carrier
organic anion
transporter family,
member 1B1
(SLCO1B1)
genotype
Carriers of the
SLCO1B1*5
variant : increased
risk of statin
myopathy, most
consistently with
simvastatin due to
impaired hepatic
influx & increased
plasma
concentrations of
statins
Benefit from
alternative statin
(e.g. Rosuvastatin)
Overview of Approaches to Personalize
Pharmacotherapeutic Management in Vascular Medicine
Pharmacotherap
eutic Area
Therapeutic
Question
Guiding Tests
Potential
Personalized
Intervention
Lipid-lowering
therapy
Benefit of
fenofibrate
Apolipoprotein
A5 (ApoA5)
genotype
carriers of the
APOA5 SNP 56G :
greater benefit
from fenofibrate
therapy : more
pronounced
increases in HDL
& decreases in
fasting &
postprandial
triglycerides
Benefit of
ezetimibe
Niemann- Pick
C1 Like (NPC1L1)
Carriers of the
NPC1L1 : greater
benefit from
ezetimibe : more
pronounced
reductions in LDL
Lipid lowering therapy
Even in high risk patients, trials of fenofibrate as
monotherapy or combination add-on therapy to statins
have failed to show a reduction in macrovascular
events.
The Study of Heart & Renal Protection (SHARP) trial :
17% reduction in atherothrombotic events among
patients with CKD randomized to simvastatin &
ezetimibe vs placebo. (not designed to compare
ezetimibe plus statin to statin monotherapy alone)
Combination therapy, statin plus fibrates, niacin,
& ezetimibe has yet to demonstrate an incremental
clinical outcome benefit above & beyond statin
monotherapy in randomized controlled studies
Journal of SVM
Vol 16,no.5, 2011
Incidence of CV events in secondary
prevention cohorts : 20% after 4 – 5 years
even with intensive treatment & vigilant
monitoring
It is not clear that evaluating SLCO1B1
status would confer an advantage over
current precautions to minimize stainrelated muscle side effects
Overview of Approaches to Personalize
Pharmacotherapeutic Management in Vascular Medicine
Pharmacotherap
eutic Area
Therapeutic
Question
Guiding Tests
Potential
Personalized
Intervention
Antithrombotic
Therapy
Warfarin dosing
Cytochrome
P450 2C9
(CYP2C9)
genotype
Carriers of
CYP2C9 variants
CYP2C9*3 and
CYP2C9*2 :
slower warfarin
metabolism &
require lower
maintenance &
cumulative
induction doses
of warfarin
Antithrombotic Therapy
CYP2C9 metabolizes S-warfarin : 3-5 times more
potent than R-warfarin

warfarin : racemic mixture of S and Renantiomers
 CYP2C9*3 and CYP2C*2 alleles : significantly
reduce CYP2C9 enzyme activity
slower
warfarin metabolism, carriers require lower
maintenance and cumulative induction doses

susceptible to supratherapeutic INRs, increase
the risk of serious or life threatening bleeding

deGoma, et.al.
J of Vasc med vol 16,no.5, 2011
Overview of Approaches to Personalize
Pharmacotherapeutic Management in Vascular Medicine
Pharmacotherap
eutic Are
Therapeutic
Question
Guiding Tests
Potential
Personalized
Intervention
Antithrombotic
Therapy
Warfarin dosing
Vitamin K
epoxide
reductase
complex
(VKORC1)
genotype
Carriers of the A
allele at position
1639 of the
VKORC1 gene
require lower
maintenance &
cumulative
induction doses
of warfarin. The
VKORC1 gene
encodes the
target enzyme of
warfarin’s
anticoagulant
effect
Antithrombotic Therapy
VKORC1: target enzyme of warfarin
recycles the oxidized form of vit K to its
reduced form , cofactor for gamma-glutamyl
carboxylation necessary for activation of factors
11, V11, 1X, and X

gene polymorphisms of VKORC1: significant
impact on individual & interethnic daily warfarin
dose requirements

higher frequencies of VKORC1 SNPs
1173TT & 1639AA among Asians :
heightened sensitivity to warfarin


deGoma, et.al.
J of Vasc med vol 16,no.5, 2011

Translation to routine clinical practice
awaits the results of ongoing randomized
clinical trials comparing personalized
approaches with standard of care
management