“best” medical management for pad€¦ · - randomized pts with cv disease to vorapaxar vs....

“Best” Medical Management of PAD

Heather L. Gornik, MD, RVT, RPVIUniversity Hospitals Cleveland Medical Center

2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease

Developed in Collaboration with the American Association of Cardiovascular and Pulmonary Rehabilitation, Inter-Society Consensus for the Management of Peripheral Arterial Disease, Society for Cardiovascular Angiography and Interventions, Society for Clinical Vascular Surgery, Society of Interventional Radiology, Society for Vascular Medicine, Society for Vascular Nursing, and Vascular and Endovascular Surgery Society

Management of PAD: A Three-Pronged Approach

Managementof the Patient

with PAD

Protect the Feet: Prevent Amputation

Improve Function and

QOL

Prevent MI, Stroke, and

Death

• Patients with PAD + diabetes at highest risk for amputation

• Remove the socks and examine the feet at each visit • Reinforce importance of meticulous foot and nail care at

each visit• Encourage daily foot self-inspection• Appropriate footwear (orthotics, diabetic shoes)• Collaboration with podiatry • Review warning signs of acute and critical limb ischemia

at each visit• The concept of “leg attack”• Advise patients to call in to report an ulcer or rest

pain; advise nursing and support staff to take these calls seriously


with PADProtect the

Feet: Prevent Amputation


QOL


Death

PAD Medical Therapy: Protect the Feet and Prevent Amputation

PAD Medical Therapy:Prevention of CV Events (+/- limb events)• Smoking cessation • Antiplatelet + antithrombotic Rx• Statins• Antihypertensive therapy

• ACE inhibitors or ARBs • Glycemic control for diabetic patients• Influenza vaccination


with PAD



QOL


Death

Emerging concept:Some Rx to prevent CV events may also prevent limb events

Smoking Cessation• Single most important intervention for PAD patients• Improves survival and limb outcomes among symptomatic PAD patients1-6

• Treadmill walking time, revascularization, amputation

• Multiple agents available for pharmacologic support• Nicotine replacement, buproprion, varenicline

• Intensive smoking cessation programs, including pharmacotherapy and counseling, improve abstinence rates in PAD patients7

• 21.3% (intensive) vs 6.8% (minimal) at 6 months7

• Very limited data on use of e-cigs to quit standard cigs; evolving area of research. Stay tuned.

1Lasila R, et al. Acta Chir Scand. 1988;154:635. 2Jonason T, et al. Acta Med Scand. 1987;221:253. 3Willigendael, et al. J Vasc Surg. 2005;42:67. 4Gardner AW. Vasc Med. 1996;1:181. 5Quick CR, et al. Br J Surg. 1982;69:S24. 6Faulkner KW. Med J Aust. 1983;1:217. 7Hennrikus D, et al. J Amer Coll Cardiol. 2010;56:2105.

“Traditional” Anti-platelet Rx: Evidence from RCTs• Reduced CV event rate by 25% ↓ in large meta-analysis1

• Incremental benefit of clopidogrel vs aspirin in CAPRIE trial2

• Large RCTs question benefit of aspirin alone for prevention of events in asymptomatic patients with abnormal/borderline ABI (POPADAD3, AAA4 trials)

• 2009 meta-analysis (Berger, et al.) suggests aspirin not adequately proven to be anti-platelet agent of choice for preventing CV events in PAD patients5

• Ticagrelor not superior to clopidogrel for patients with PAD (EUCLID trial)8

• Inconsistent benefit of DAPT in PAD with increased bleeding risk9,10

1Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71. 2CAPRIE Steering Committee. Lancet. 1996;348:1329. 3Belch J, et al. BMJ. 2008;337:1840. 4Fowkes FGR, et al. JAMA. 2010;303:841. 5Berger JS, et al. JAMA 2009;301:1909. 6Heart Protection Study. Lancet. 2002;360:7. 7HPS Collaborative Group. J Vasc Surg. 2007;45:645. 8Hiatt WR, et al. 2017 N Engl J Med. 9Cacoub PP, et al. Eur Heart J. 2009;30:192. 10Belch JJ, et al. J Vasc Surg. 2010;52:825.

2016 PAD Guideline: Antiplatelet AgentsCOR LOE Recommendations

I A

Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD.

IIa C-EOIn asymptomatic patients with PAD (ABI ≤0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death.

IIb B-RIn asymptomatic patients with borderline ABI (0.91–0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain.

Gerhard-Herman MD, et al. 2016 AHA/ACC PAD Guideline. Co-published: Circulation 2017;135:e726. J Am Coll Cardiol. 2017;69:e71.

2016 PAD Guideline: Antiplatelet RxCOR LOE Recommendations

IIb B-R

The effectiveness of dual-antiplatelet therapy (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established.

IIb C-LD

Dual-antiplatelet therapy (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization.


Novel Anti-Platelet Rx: Vorapaxar•FDA approved May, 2014•Thrombin receptor antagonist; inhibits platelet activation by thrombin via protease activator-receptor 1 (PAR-1) 1

•Used in addition to aspirin or clopidogrel, not alone•Very long t1/2 - drug effect present 4 weeks after last dose and no antidote or reversal agent1

•Encouraging data from TIMI-50 Trial2

- Randomized pts with CV disease to vorapaxar vs. placebo (all on std. anti- PLT therapy)- PAD subset N=3,787 patients (claudication + abnormal ABI or prior LE revasc)- No benefit of vorapaxar vs. placebo on 1◦ composite endpoint CV death, MI, stroke at 3

years median f/u - BUT statistically significant ↓in hospitalization for ALI (adjudicated) or LE revascularization- Cost: ↑ moderate to severe bleeding with vorapaxar: 7.5% vs 4.5% (p = 0.001)

1Vorapaxar package insert. 2Bonaca MP et al. Circulation. 2013;127:1522.

2016 PAD Guideline: Antiplatelet Rx

COR LOE Recommendations

IIb B-RThe overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain.


New Concept: Low Dose Antithrombotic + Antiplatelet Rx for PAD - COMPASS Trial

• Landmark RCT to assess the efficacy of rivaroxaban (oral αXa inhibitor) alone or in addition to aspirin for prevention of CV events in patients with CAD, PAD, CAS

• Randomized patients with PAD, CAD (+ other high risk features), CAS to 3 Rx arms:

• ASA 100 mg/day + placebo BID• Rivaroxban 5 mg BID (low dose) + placebo QD (no aspirin)• ASA 100 mg/day + rivaroxaban 2.5 mg BID (very low dose)

• Pts. Not on a PPI randomized to pantoprazole or placebo• 1° efficacy endpoint CV death + MI + stroke• Study stopped 13 months early by DSMB (for efficacy) with 27,395 patients

enrolled J.W. Eikelboom, et al. N Engl J Med. 2017;377:1319.

COMPASS Trial: PAD Patient Subgroup• Among 7,470 pts. with PAD (+CAS):

combination aspirin + riva ↓ 1◦

endpoint of CV death/MI/stroke (HR = 0.72, p=0.005)1

• Among 6,391 pts. with significant PAD aspirin + Riva ↓ in MALE vs. placebo2

• ↓ major amputation (HR=0.33, p=0.03)

• ↓ vascular intervention (HR=0.76, P=0.03)

• ↓ALI+CLI+vasc hosp. (HR=0.76,P=0.02)

• Cost: ↑risk of major bleeding with aspirin + riva vs. aspirin alone (HR=1.61, p=0.01)1Anand SS, et al. Lancet. 2017;377:1319.2Anand SS, et al. J Am Coll Cardiol. 2018;2306.

MACE

MALEALICLI

Vasc Hosp

1Heart Protection Study. Lancet. 2002;360:7. 2HPS Collaborative Group. J Vasc Surg. 2007;45:645. 3Mohler E, et al. Circulation 2003;108:1481. 4Giri J, et al. J Am Coll Cardiol. 2006;47:998. 5Abbruzzese TA, et al. J Vasc Surg. 2004;39:1178. 6Westin GG, et al. JACC. 2014;63:682. 7Poldermans, et al. Circulation. 2003;107:1848. 8Durazzo AE, et al. J Vasc Surg. 2004;36:967. 9Feringa HH, et al. J Amer Coll Cardiol. 2007;50:1649. 10Schouten O, et al. N Engl J Med. 2009;361:980. 11Khumbani DJ, et al. Eur Heart J. 2014;35:2864.

•Statins- 24% ↓ in first major vascular event in Heart Protection Study (HPS)3

- 20% ↓ in non-coronary revascularization (HPS)4

- Improve claudication in single-center and 1 multi-center study3

- May slow rate of functional decline among patients with PAD4

- Use associated with improved patency of infrainguinal bypass grafts and infrapopliteal PTA sites for CLI5,6

- Use associated with decreased perioperative complication rate among patients undergoing major vascular surgery7-10

- Real world data from REACH Registry confirms significant ↓ in MACE, all cause mortality, MALE with statin Rx for patients with PAD11

Statins and PAD: Evidence from RCTs

2016 PAD Guideline: Statin Rx

COR LOE Recommendation

I A Treatment with a statin medication is indicated for all patients with PAD.


New Data: PCSK9 Inhibitors and “Extreme” LDL Lowering for PAD? Sub-analysis of the FOURIER Trial

• N=27,564 Pts. with prior MI/stroke/PAD randomized to evolocumab vs. placebo on background statin Rx

• Median f/u 2.2 years

• Report of subgroup of N=1,505 pts with sx PAD without hx of MI or stroke

• Evolocumab lowered LDL with from median 94 mg/dL 31 mg/dL

• Evolucumab ↓MACE vs. placebo (HR 0.79, P=0.0098)

• Evolucumab ↓MALE vs. placebo (HR =0.63, P=0.063)

• No signal of adverse events with evolocumab

• MACE benefit greater among patients with PAD than those without PAD

Bonaca MP, et al. Circulation. 2018;137:338.

BP Control to Prevent CV Events in PAD: Evidence from RCTs

• Intensive blood pressure control • Data strongest for ace-inhibitors (HOPE1), ARBs (ONTARGET2) both

showing ↓ MACE• Ramipril dramatically improved treadmill walking times (77%-123%)

and QOL scores in Australian multi-center study of patients with claudication3 --- Unfortunately, study recently retracted

• Strong protective effect of intensive BP lowering in diabetics with PAD (ABCD4)

• Beta blockers can (and should) be used in PAD patients when indicated

• Do not worsen claudication in 11 trial meta-analysis5

• Shown to improve treadmill walking times 1 in single center study6

1HOPE Study. N Engl J Med. 2000; 342:145. 2ONTARGET Study. N Engl J Med. 2008;358:1547. 3Ahimastos AA, et. al. JAMA. 2012;309:453. 4Mehler, et al. ABCD Trial. Circulation. 2003;107:753. 7Radack K, et al. Arch Intern Med. 1991;151:1769. 6Espinola-Klein C, et al. Hypertension. 2011;58:148.

2016 PAD Guideline: Antihypertensive TherapyCOR LOE Recommendations

I AAntihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure, and cardiovascular death.

IIa AThe use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers can be effective to reduce the risk of cardiovascular ischemic events in patients with PAD.


1Selvin E, et al. Diabetes Care 2006;29:877.2Resnick, et al. Diabetes Care. 2004;27:1885. 3Takahara M, et al. Diabetes Care. 2010;33:2538. 4Singh S, et al. Vasc Med 2014;19:307.

•Epidemiological studies (ARIC, Strong Heart) have demonstrated ↑ risk of major limb events and amputation among patients with PAD with poor glycemic control1,2

•Large RCTs have yet to demonstrate a significant benefit of stringent glycemic control protocols on limb outcomes among diabetic patients with PAD

•However, recent observational data from case series/cohort studies of CLI suggests benefit of glycemic control among diabetics with CLI undergoing revascularization

- Kansai Rosai Hospital, Japan (N=278 patients)3; adjusted HR for major amputation with HgB A1c > 6.8% = 2.9

- UC Davis CLI Registry (N=149) patients4; patient with FGB < median 144 mg/dL at time of PTA with ↑ vessel patency (various parameters), ↓ rate of major amputation, ↓ surgical revascularization at 1 year follow-up

Evidence from the Literature: Glycemic Control and PAD

2016 PAD Guideline: Glycemic ControlCOR LOE Recommendations

I C-EOManagement of diabetes mellitus in the patient with PAD should be coordinated between members of the healthcare team.

IIa B-NR Glycemic control can be beneficial for patients with CLI to reduce limb-related outcomes.


New Data: Diabetes Medications and Amputation Risk• A number of new oral agents are available to treat T2DM• Emerging data on use of these agents to reduce CV risk have had some surprising

signals in terms of amputation risk• Sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (CANVAS trial)

↓ risk of major CV event but was associated with an ↑ risk of amputation vs. placebo during mean f/u of ~ 3.6 yrs1

• SGLT-2 inhibitor empagliflozin (EMPA-REG OUTCOMES trial) also ↓ risk of major CV events (including CV death) among pts with T2DM but not found to have signal of amputation risk (median f/u 3.1 yrs)2,3

• New data: glucacon-like peptide 1 (GLP-1) liraglutide (LEADER trial) 35% RR ↓ amputation vs. placebo among patients with T2DM (up to 5 yr f/u)4

• But no difference in % diabetic foot ulceration, peripheral revascularization1Neal B, et al. N Engl J Med. 2017;377:644. 2Zinman B et al. N Engl J Med. 2015;373:2117. 3Ianzucchi, SZ, et al. Diabetes Care. 2018;41:e4. 4Dhatariya K et al. Diabetes Care 2018;41:2229.

https://www.ncbi.nlm.nih.gov/pubmed/28605608

2016 PAD Guideline: Influenza Vaccination

COR LOE Recommendation

I C-EO Patients with PAD should have an annual influenza vaccination.


Known CAD % Lipid lowering Rx

% Anti-platelet Rx

Other

PARTNERS (1999)1

Primary Care Setting N=366 known PAD

Excluded 56% 54%

Rehring, et al. (2005)2

Kaiser Colorado RegionN=1,733 known PAD

Excluded 31% (statin) n/a54% diabetics with HgB A1c>7.0%32% ACE-I or ARB

REACH Registry (2006)4

N=8,273 symptomatic PADIncluded 70% 82% 70% ACE-I or ARB

NHANES survey (2011)5

N=451 ABI < 0.90Excluded(all CVD)

18% (statin) 27% 21% ACE or ARB

BCBS Michigan BMC2 PVI Registry (2014)6

N=4,459 CLI patients post revascularization

PAD only

PAD + CAD/CVD

62% statin

80% statin

92%

96%

53% ACE/ARB

64% ACE/ARBBerger JS and Ladapo JA (2017)7

National/National Hospital Ambulatory Medical Care Surveys (2017)7

N~1,500 pt office visits

Excluded 31% statin 33% 29% Ace-I or ARB

And This Seems So Obvious…

1Hirsch AT, et al. PARTNERS Study. JAMA. 1999;286:1317. 2Rehring TF, et al. J Vasc Surg. 2005;41:816. 3Conte MS, et al. J Vasc Surg. 2005;42:456. 4Bhatt DL, et al. JAMA. 2006;295:180. 5Pande RL, et al. Circulation. 2011;124:17. 6Krishnamurthy V, et al. Vasc Med. 2014;19:491.7Berger JS. J Am Coll Cardiol; 2017:69:2293.

PAD Medical Therapy: Improve Function and QOL

• Cilostazol• Structured Exercise Therapy

• RevascularizationManagementof the Patient

with PAD



QOL


Death

Cilostazol• FDA approved 1999• Phosphodiesterase type III inhibitor (⇑cAMP) • Dosed 100 mg bid (50 mg tablet also available, use with interacting medications,

eg, CYP 3A4, CYP2C19)• Multiple pharmacologic properties

• Weak antiplatelet, weak vasodilator, some positive benefits on lipid profile,1

may prevent intimal hyperplasia/restenosis of stents2,3

• Uncertain mechanism of action in helping symptoms of claudication• BLACK BOX WARNING: Cilostazol is contraindicated in patients with congestive

heart failure of any severity• Side effects of cilostazol are common4

• Abnormal stools or diarrhea (~15-20%)• Palpitations or tachycardia (~15%)• Headaches (25-35%)

2010 Pooled Analysis of 9 trials in 2491 patients (Pande RL, et al. Vasc Med 2010.15;181):

Cilostazol 100 mg BID↑ maximal walking distance by 50.7% vs 24.3% for placebo

1Elam MB, et al. ATVB. 1998;18:1942. 2Douglas JS, et al. Circulation. 2005;112:2826. 3Soga Y, et al. J Amer Coll Cardiol. 2009;53:48. 4Cilostazol package insert.

Dawson DL, et al. Am J Med. 2000;109:523.

From Drs. Dawson, Strandness and colleagues

Pharmacologic Therapy for Claudication

N=698 patientsAt 54 clinics

P<0.001 vs pentoxifylline

Weeks of Treatment

Cilostazol 100 mg 2x/day (n=227)Pentoxifylline 400 mg 3x/day (n=232)Placebo (n=239) *

*

0

10

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40

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Dawson DL, et al. Am J Med. 2000;109:523.

2016 PAD Guideline: Cilostazol, Pentoxifylline, and Chelation Therapy

COR LOE RecommendationsCilostazol

I ACilostazol is an effective therapy to improve symptoms and increase walking distance in patients with claudication.

PentoxifyllineIII: No

Benefit B-R Pentoxifylline is not effective for treatment of claudication.

Chelation TherapyIII: No

Benefit B-R Chelation therapy (eg, ethylenediaminetetraacetic acid) is not beneficial for treatment of claudication.


Multiple Potential Mechanisms of Benefit of Exercise in PAD• Improves endothelial function• Modifies muscle metabolism in the setting

of hypoxia• Improves biomechanics / gait efficiency• Reduces inflammation and reactive oxygen

species• Decreases blood viscosity• Improves multiple CV risk parameters• Stimulates angiogenesis for collateral formation• Improved CV conditioning Stewart KJ, et al. N Engl J Med. 2002;347:1941

Bonaca MP and Creager MA. Circ Res. 2015;116:1579.Hamburg NM and Balady GJ. Circulation. 2011;123:87.Figure from Bonaca MP and Creager MA. Circ Res. 2015;116:1579.

Supervised Exercise Rehabilitation for PAD• Improves exercise performance, walking ability, physical functioning,

and QOL• Up to 180% ↑PFWD (180 meters)2-4

• 120-150% ↑ MWD (128 meters) in meta-analyses2-4

• Improved quality of life SF-36 physical component summary scores1,5

• Safe• Highly cost-effective when compared to catheter-based

revascularization6

1Stewart KJ, et al. N Engl J Med. 2002;347:1941. 2Gardner AW, et al. JAMA. 1995;274:975. 3Leng GC, et al. CochraneReview. 2000. CD000990. 4Fakhry F, et al. J Vasc Surg. 2012;56:1132. 5Parmenter BJ, et al. Vasc Med. 2015. 6Treesak C, et al. Vasc Med. 2004 9:279.

5.2017: Supervised Exercise Therapy for PAD now Covered by Medicare!

Source: www.cms.gov

2016 PAD Guideline: Structured Exercise TherapyCOR LOE Recommendations

I AIn patients with claudication, a supervised exercise program is recommended to improve functional status and QoL and to reduce leg symptoms.

I B-RA supervised exercise program should be discussed as a treatment option for claudication before possible revascularization.

IIa A

In patients with PAD, a structured community- or home-based exercise program with behavioral change techniques can be beneficial to improve walking ability and functional status.

IIa A

In patients with claudication, alternative strategies of exercise therapy, including upper-body ergometry, cycling, and pain-free or low-intensity walking that avoids moderate-to-maximum claudication while walking, can be beneficial to improve walking ability and functional status.


Emergent/urgent revasc

Acute limb ischemia

Critical limb ischemia

Risk Benefit Discussion + Shared Decision Making

Vocational necessity

Lifestyle-limited claudicant, failed medical therapy

Lifestyle-limited claudicant, favorable anatomy for revascularization

Indications for Revascularization Not Indicated Asymptomatic low

ABI

The non-limited claudicant


with PAD



QOL


Death

Management of PAD: A Three-Pronged Approach

“best” medical management for pad€¦ · - randomized pts with cv disease to vorapaxar vs....

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