Medical Management of PAD: What Do You Need to...
Transcript of Medical Management of PAD: What Do You Need to...
Medical Management of PAD: What Do You Need to Know?
Matthew Menard, MD
Brigham and Women’s Hospital
DISCLOSUREMatthew Menard, MD
• Advisory Board: Janssen Pharmaceuticals
CDC Trends in 2 Major PAD Risk Factors
Trends in age-standardized rates of diabetes
mellitus–related complications, 1990 to 2010.
Beckman, JA Circ Res. 2016;118:1771-1785
Trends in Rates of Lower Extremity Amputation Among Dialysis Patients With ESRD
JAMA Intern Med. 2018;178(8):1025-1032
Retrospective study of 3 700 902 records from a US national registry of ESRD/Dialysis patients with assessed cross-sectional cohorts for each calendar year from 2000 through 2014
Trends in Rates of Lower Extremity Amputation Among Dialysis Patients With ESRD
Retrospective study of 3 700 902 records from a US national registry of ESRD/Dialysis patients with assessed cross-sectional cohorts for each calendar year from 2000 through 2014
JAMA Intern Med. 2018;178(8):1025-1032
REDUCE RISK OF
CARDIOVASCULAR EVENTS
REDUCE RISK OF
LIMB EVENTS
IMPROVE SYMPTOMS &
QUALITY OF LIFE
Medical Management of PAD
IMPROVE SYMPTOMS &
QUALITY OF LIFE
- Supervised exercise program
- Cilostazol
- Statins
REDUCE RISK OF
CARDIOVASCULAR EVENTS
REDUCE RISK OF
LIMB EVENTS
Medical Management of PAD
• The standard 12-week supervised
exercise improves exercise
performance and QOL in PAD
patients.
• Exercise training is associated
with decreased all-cause and
cardiovascular mortality.
Treat-Jacobson D et al. Circulation. 2019 Jan 22;139(4):e10-e33
Chang P. et al. Mayo Clin Proc 2015;90:339–45
Improvement in Symptoms and QOL
.Gerhard-Herman M et al. Circulation. 2017;135:e686–e725
Supervised exercise
Olin JW et al. JACC. 2016;67:1138-57
• Cilostazol - phosphodiesterase III inhibitor improves
claudication, through unknown mechanism.
• Improves walking distance approximately 50% cf placebo
• Also 1A recommendation
• May require up to 4 4
months to achieve full
clinical effect
• Troublesome side effects.cilostazol
Cilostazol
IMPROVE SYMPTOMS &
QUALITY OF LIFE
- Supervised exercise program
- Cilostazol
- Statins
REDUCE RISK OF
CARDIOVASCULAR EVENTS
REDUCE RISK OF
LIMB EVENTS
- HgA1C < 7
- Aspirin or plavix
- Statins
- Tobacco cessation
- ACE-inhibitors/ARBs
- PCSK9 inhibitor (evolocumab)
- Aspirin + rivaroxaban
Medical Management of PAD
Ratchford EV. J Vasc Surg. 2017;66:275-80
• Up to 80% of patients with PAD are current or former
smokers.
• Smoking after lower extremity bypass increases the risk
of graft failure 3X.
Smoking Cessation
Conen D et al. Ann Intern Med. 2011;154:719–726
Smoking cessation reduces the risk of incident PAD
Smoking Cessation
Barua RS et al. JACC 2018, 72 (25) 3332-3365
Smoking Cessation
Barua RS et al. JACC 2018, 72 (25) 3332-3365
Smoking Cessation
Barua RS et al. JACC 2018, 72 (25) 3332-3365
Smoking Cessation
• HOPE trial: ACE inhibition associated with significant
reduction in MACE among PAD patients.
• Ramipril’s effects were seen in both asymptomatic and
symptomatic PAD across a broad range of ABI values.
• Similar effects were seen with telmisartan in the
ONTARGET trial.
HOPE N Engl J Med 2000;342:145–53 – ONTARGET N Engl J Med 2008;358:1547–59
CV Risk Reduction: ACE-Is/ARBs
IMPROVE SYMPTOMS &
QUALITY OF LIFE
- Supervised exercise program
- Cilostazol
- Statins
REDUCE RISK OF
CARDIOVASCULAR EVENTS
REDUCE RISK OF
LIMB EVENTS
- Tobacco cessation
- Aspirin or a thienopyridine
- Statins
- ACE-inhibitors/ARBs
- PCSK9 inhibitor (evolocumab)
- Aspirin + rivaroxaban
- Statins
- PAR-1 antagonist (vorapaxar)
- PCSK9 inhibitor (evolocumab)
- Aspirin + low dose
rivaroxaban
Medical Management of PAD
Kumbhani DJ et al. Eur Heart J. 2014;35:2864–2872
Reduction of Limb Events: Statins
Days from Randomization
MA
CE
(%
)
Vorapaxar
10.7%
Placebo
12.5%
HR 0.85
(0.73-0.99)
P=0.034
3 Y
rK
M E
sti
ma
te
1.8% ARR
NNT 56
Vorapaxar and MACE in Patients with PAD
ISTH Major Bleeding HR 1.39, p<0.001GUSTO Mod/Severe 1.62 p=0.001
No significant increase in ICH or Fatal Bleeding
Vorapaxar and Limb Vascular Efficacy
Hospitalization for Acute Limb IschemiaPre-specified, adjudicated
2.3%
3.9%
Hazard Ratio 0.5895% CI 0.39 to 0.86
p = 0.006
Placebo
Vorapaxar
N = 3767
Days from randomization
Peripheral Revascularization
Prespecified, Investigator
18.4%
22.2%
Hazard Ratio 0.84;95% CI 0.73 to 0.97
p = 0.017
Bonaca et al. Circulation 2012
Summary of Effects of PCSK9i Evolocumab
• LDL-C by 59% to a median of 30 mg/dL• CV outcomes in patients on statin• Safe and well-tolerated
14.6
9.9
12.6
7.9
0
5
10
15
KM
Rat
e (
%)
at 3
Ye
ars
HR 0.85 (0.79-0.92)
P<0.0001
HR 0.80 (0.73-0.88)
P<0.0001
CVD, MI, stroke
UA, cor revasc
CVD, MI, stroke
Sabatine MS et al. NEJM 2017;376:1713-22
Evolocumab
(median 30 mg/dl, IQR 19-46 mg/dl)
Placebo
59% reduction
P<0.00001
Absolute 56 mg/dl
0%
2%
4%
6%
8%
10%
12%
0 90 180 270 360 450 540 630 720 810 900
CV
De
ath
, MI o
r St
roke
Days from Randomization
Placebo
Evolocumab
10.3%
5.5%
PAD4.8% ARRNNT2.5y 21
PAD (no MI/stroke, N=1505)
43% RRR
HR 0.57(0.38 – 0.88)
P=0.0095
CV Death, MI or Stroke in Patients with PAD and no MI or Stroke
Maj
or
Ad
vers
e Li
mb
Eve
nts
Placebo
0.45%
0.0%
0.1%
0.2%
0.3%
0.4%
0.5%
0 90 180 270 360 450 540 630 720 810 900
Days from Randomization
Major Adverse Limb Events
Placebo
Evolocumab
0.45%
0.27%
All PatientsN=27,564
42% RRR
HR 0.58(0.38 – 0.88)
P=0.0093
0.0%
0.1%
0.2%
0.3%
0.4%
0.5%
0 90 180 270 360 450 540 630 720 810 900
Days from Randomization
Bonaca et al. Circulation 2018
Maj
or
Ad
vers
e Li
mb
Eve
nts
Placebo
0.45%
0.0%
0.1%
0.2%
0.3%
0.4%
0.5%
0 90 180 270 360 450 540 630 720 810 900
Days from Randomization
Major Adverse Limb Events
Placebo
Evolocumab
0.45%
0.27%
All PatientsN=27,564
42% RRR
HR 0.58(0.38 – 0.88)
P=0.0093
0.0%
0.1%
0.2%
0.3%
0.4%
0.5%
0 90 180 270 360 450 540 630 720 810 900
Days from Randomization
Bonaca et al. Circulation 2018
Outcome HR 95% CIMALE 0.58 (0.38–0.88)
ALI or major amputation 0.52 (0.31–0.89)ALI 0.55 (0.31–0.97)
Major amputation 0.57 (0.17–1.95)Urgent revascularization 0.69 (0.38–1.26)
0%
2%
4%
6%
8%
10%
12%
14%
0 90 180 270 360 450 540 630 720 810 900
Placebo
12.8%
6.5%
PAD6.3% ARRNNT2.5y 16
Days from Randomization
MACE or MALE in Patients with Just PAD
MA
CE
or
MA
LEPAD
(no MI/stroke, N=1505)
48% RRR
HR 0.52(0.35 – 0.76)
P=0.0006
Bonaca et al. Circulation 2018
Evolocumab
Adapted from: N Engl J Med 2007;357:217-27.
COMPASS Trial PAD+CAD
>90% with CAD, large subgroup with
Concomitant PAD
28% Reduction in MACE
70% Increase in Major Bleeding
Anand SS et al. Lancet. 2018 Jan 20;391(10117):219-229
COMPASS: Reduction of Limb Events
VOYAGER PAD: Study Design
Multicenter, randomized, double-blind, placebo-controlled, event-driven phase III study
Primary efficacy outcome: CV death, MI, ischemic stroke, acute limb ischemia, and major amputation
Principal safety outcome: TIMI Major Bleeding
Event driven (~1015 PEP)
Pts age ≥ 50 yo with:• Documented moderate to severe PAD with ABI <0.90 and angiographic or imaging evidence of occlusive PAD
•Any vascular surgical
bypass to the lower
extremity including aorto-
iliac, infra-inguinal, and
extra-anatomic bypass for
symptomatic PAD
•Clinical indication to treat
symptomatic PAD with
peripheral revascularization
to restore limb perfusion
Exclusion criteria : Rutherford category 0, 1, & 6; endovascular revascularization of the aorto-iliac segment without any additional revascularization below the inguinal ligament; general criteria based on known rivaroxabancontraindication such as allergy, known bleeding diathesis, etc.
Rivaroxaban 2.5 mg bid + ASA 100 mg od
T0, Day 1
R
1 month post study
drugobservation
period
Treatment Phase
(mean treatment duration of 30 months,
maximum 42 month)
Placebo + ASA 100 mg od
post-procedural concomitant thienopyridines allowed for a maximum period of 30 days
1:1 randomization*
Revascularization procedure
(surgery or endovascular)
Screening Phase Wash-out,
Safety FU
*Onset of study drug treatment after revascularization procedure
N = 6500
Capell W, Bonaca MP, …Hiatt WR et al. AHJ in Press
BASIL 1: Mortality
Adam DJ et al. Lancet 2005; 366:1925-34.
At 5.5 years of follow up, overall mortality was 37%
Years of follow-up
Current outcomes highly significantly worse than BASIL-1 (p = 0.0001)
BASIL-1 (1999-2003)
HEFT (2009-2013)
D30
%
At 7 years of follow up, overall mortality was 67%
BASIL 1: Mortality
Yes, Real Potential to Change Outcomes
More Potent Antithrombotic Therapy:• Reduces MACE with clearest benefit in patients with polyvascular disease: PAD & CAD
• Reduces MALE and Amputation (greatest benefit after revascularization)
Achieving Very Low LDL-C (~30 mg/dL) • Reduces MACE
• Reduces MALE
• Safe
Has Medical Therapy for PAD Come of Age?
Conclusion• Most vascular surgeons have varying degrees of awareness of high impact
medical trials (CAPRIE, TIMI-50, TIMI-54, EUCLID, COMPASS, FOURIER) • From dim to less dim
• Highlights importance and value of collaboration between cardiology, vascular medicine and vascular surgery
• For patient care
• For future trials
• Diabetic patients will represent ever greater proportions of the patients with CLI
• Current PAD-associated MACE and MALE considerable
• New agents are costly, but can significantly reduce both MACE and MALE
• Better medical care, smoking cessation, and novel medical therapies will reduce adverse limb events following both endo and open revascularization