Cessation of all antiplatelet therapies after PCI, at any time, for any stent, is associated with an increased risk

of thrombotic events, including late stent thrombosis. These events are likely to occur within 7 to 30 days of drug discontinuation.

Cessation of clopidogrel (alone) during the early period after PCI (within 30 days of either DES or BMS placement) is associated with an increased risk of thrombotic events.

Cessation of clopidogrel (alone) beyond 30 days from the time of BMS placement is common in clinical practice and does not confer increased risk of thrombosis over a brief period of time. There is likely benefit from more prolonged dual platelet antagonists among patients with ACS undergoing PCI.

Cessation of clopidogrel (alone) upon completion of 6 months of treatment after DES placement is controversial (in terms of long-term risk) but does not seem to confer a significant short-term risk (within the subsequent 30 days) in a majority of patients if aspirin is continued.

Shortacting platelet P2Y12 inhibition with reversible agents like cangrelor or ticagrelor (not available for clinical use at the present time) or an alternative compound with similar properties of target selectivity and a very short biological half-life represents the most attractive platform for bridging therapy. The BRIDGE (Maintenance of Platelet inihiBition With cangRelor After dIscontinuation of ThienopyriDines in Patients Undergoing surgery) trial (ClinicalTrials identifier: NCT00767507) will compare cangrelor and placebo among 200 patients in whom a thienopyridine drug is discontinued before coronary artery bypass grafting.

The dose of clopidogrel (300 mg or 600 mg) should be gauged by individual patient risk, to include the presence of a coronary stent, the type of stent (BMS or DES), and how recently the stent was placed.

3 A Practical Approach to Managing Cardiovascular Risk and Bleeding Complications Avoid cessation of all antiplatelet therapies after PCI with stent placement when possible. Avoid cessation of clopidogrel (even when aspirin is continued) within the first 30 days after PCI and either DES or BMS placement when possible. Defer elective endoscopic procedures, possibly up to 12 months, if clinically acceptable from the time of PCI and DES placement. Perform endoscopic procedures, particularly those associated with bleeding risk, 57 days after thienopyridine drug cessation. Aspirin should be continued when possible. Resume thienopyridine and aspirin drug therapy after the procedure once hemostasis is achieved. A loading dose of the former should be considered among patients at risk for thrombosis. Continue platelet-directed therapy in patients undergoing elective endoscopy procedures associated with a low risk for bleeding. .

Predictors of DES thrombosis

Urban et al, Circ 2006

Intensive Lipid Lowering and TVR (Clinical Restenosis) and Non-TVR (Lesion
TVR
p = 0.001 MV O.R. 0.63, p=0.001*

Progression)

Non-TVR

p = 0.012 MV O.R. 0.87, p=0.364*

16.0% 11.6%
%

11.3% 8.5%
%

(167/1440)

(227/1420)

(122/1440)

(227/1420)

Atorva 80 mg

Prava 40 mg

Atorva 80 mg

Prava 40 mg

* MV model adjusted for on treatment LDL

Gibson CM, ACC 2005

Management of Post PCI Patient

Dr Ashish Mishra MD,DNB (Cardiology), FACC Fellowship Interventional cardiology Mt Sinai Hospital USA Member American College Of Cardiology CHL Hospitals

Dr Ashish Mishra MD,DNB (Cardiology) Fellowship Interventional cardiology USA CHL Apollo Hospital

Percutaneous coronary intervention (PCI) an effective revascularization strategy for CAD since its inception in 1977. 1.2 million PCIs performed/yr US, and 45,000 per year in the UK. India - Exact figures not available but number is increasing day by day due to widening indications

The rapid technological advances & widening indications for PCI means that new techniques, along with their new complications, are seen ever more frequently.

Hence the need for regular review and updates for clinicians involved in the care of these patients

Stent thrombosis after 1 year was more common with both sirolimus-eluting stents and paclitaxel-eluting stents than with bare-metal stents. Both drug-eluting stents were associated with a marked reduction in target-lesion revascularization. There were no significant differences in the cumulative rates of death or myocardial infarction at 4 years. Stone GW NEJM2007

Immediate post discharge care involves Detecting vascular access site complications, Dealing with contrast- induced complications, & stent thrombosis .

Long -term issues post-PCI ischemia detection and treatment of recurrent appropriate antiplatelet therapy arrhythmias and heart failure secondary prevention

Today our focus Detection & T/t of Ischemia after PCI Dual Anti platelet Therapy How long & How much What to do if your pt need Sx while on DAPT

Vascular access for PCI can be gained through the transfemoral - most commonly used transradial- becoming more popular or transbrachial techniques- very rare

In US pts usu discharged within 24 h of elective PCI. Here pt is usu discharged on the 2nd or 3rd day. Immediate post discharge care involves detecting vascular access site complications, dealing with contrast- or medication-induced complications, and stent thrombosis .

 Transfemoral access site complications ( 2-6% )

Hematoma, Pseudo-aneurysm, Arterio -venous (AV) fistula formation, Lower limb ischemia, Femoral artery infection Retroperitoneal bleeding

Mild bruises and small haematomas common do not require specific investigation or treatment. A large or enlarging lump suggests either haematoma formation or pseudo-aneurysm formation investigate with vascular ultrasound imaging .

Femoral haematoma usually resolves with time and do not require specific therapy. Pseudo-aneurysms and AV fistulas usually resolve with compression, with or without ultrasound guidance. If persists after compression, vascular surgical repair is sometimes required. The patient should be reassured about small bruises or haematomas, but large or enlarging ones should be referred back to the cardiologist

Retroperitoneal bleeding - incidence < 0.5%. results from a high needle puncture above the inguinal ligament -abdominal or back pain without any obvious haematoma formation in the groin. Clue - severe blood loss in the absence of pain, persistent hypotension. . Diagnosis confirmed by CT

CONTRAST INDUCED NEPHROPATHY With the use of non ionic dye, this complication has become less common . More common in diabetics and Pts with pre existing renal disease.

DEFINITIONS AND EPIDEMIOLOGY

No universally accepted definition

Absence of other identifiable causes 25% elevation in serum creatinine Absolute increase of 0.5 mg/dl (44 mol/L), 2 to 7 days later

Adverse short- and long-term outcomes

Unclear causal pathway to adverse cardiovascular outcome

Contrast Nephropathy

Nonoliguric & reversible SCr peaks between 2 and 5 days SCr returns to normal within 14 days Requiring dialysis: 0.4%

SUGGESTED MANAGEMENT STRATEGY

Management

Longer-term issues post-PCI very patient-specific and variable but broadly involves detection and treatment of ischemia, recurrent

arrhythmias and heart failure, appropriate antiplatelet therapy and secondary prevention.

Recurrent ischemia post-PCI can result from Restenosis,

Development of progressive disease in the same or a different coronary territory, OR

Increased myocardial demand from various causes.

Recurrent ischemia post-PCI can result from Restenosis, Development of progressive disease in the same or a different coronary territory, OR Increased myocardial demand from various causes.

Clinical restenosisOne of the major issues after PCI With BMSs around 20 % ( range 10-60%) With DES around 5-10%

occurs around 3 months post-PCI & plateaus at 12 months.

Rarely aggressive restenosis can develop

Angina that recurs > 12 months post-PCI progressive CAD in same or different coronary artery OR V. late stent thrombosis rather than restenosis

Detection of restenosis symptom status unreliable index

25% of asymt. Pts had +VE TMT ? routine stress testing in all post-PCI pts- no data However, routine stress testing - advisable 6 months post-PCI in selected cases.

Which patients to test All the symptomatic patients

Asymptomatic patients at high risk for future events stenting Non compliant patients pts with LVEF

Multivessel CAD and prox LAD

Which Test ExerciseTMT- insensitive predictor of restenosis ( 50% sensitivity), Stress testing complemented with either stress echo or nuclear perfusion (MPI) should be done.

0- 3 months post PCI Asymptomatic Clinical follow up for 3-6 months After PCI Atypical chest pain or Asymptomatic & No high risk features Continue Max Medical Therapy Stress MPI/Echo Asymptomatic with high risk features High Risk scan

Normal or low to intermediate risk scan `

Continue Clinical follow up

Repeat Stress MPI/Echo every 1-3 Years in absence of symptoms

CAG & further Mm

Post PCI Recurrent Angina Acute Chest Pain ECG ST T Changes Unchanged Low Risk High risk R/O Stent Thrombosis ECG s/o Acute MI

Stress Echo/MPI Normal or low Repeat Stress MPI/Echo every 1-3 Years Moderate high Risk scan

CAG & Further Mm

0-3 Months post PCI Asmptomatic Ct clinical follow up For 3-6 months after PCI Asymptomatic & No High risk features StressEcho/MPI

Atypical chest pain or Asymptomatic with High risk features Normal or Low To intermediate risk scan

Continue Max Medical Therapy

High Risk Scan `

Continue Clinical Follow Up

CAG & FURTHER M/M

Repeat stress MPI/Echo Every 1 to 3 years In absence of symptoms

0- 3 months post PCI Asymptomatic Clinical follow up for 3-6 months After PCI Asymptomatic & No High risk features STRESS MPI/ECHO Atypical chest pain or Asymptomatic with High risk features Normal or Low To intermediate risk scan `

Continue Max Medical Therapy

High Risk Scan

Continue Clinical Follow Up

CAG & FURTHER M/M

Repeat stress MPI/Echo Every 1 to 3 years In absence of symptoms

Post PCI Recurrent Angina ECG Unchanged ST T Changes Low Risk Stress Echo/MPI High risk ECG s/o Acute MI

Symptomatic

Acute Chest Pain

R/O Stent Thrombosis

Normal or low Risk scan

Moderate high Risk scan

CAG & Further Mm

Repeat Stress Echo/MPI Every 1 to 3 years

Post PCI Recurrent Angina ECG ST T Changes Unchanged Low Risk High risk R/O Stent Thrombosis ECG s/o Acute MI

Symptomatic

Acute Chest Pain

Stress Echo/MPI Normal or low Repeat Stress MPI/Echo every 1-3 Years Moderate high Risk scan

CAG & Further Mm

 Routine follow-up angiography is indicated only in a very few selected cases. patients who have received - left main coronary artery stenting where repeat angiography can be performed in 3-9 months. As a part of a protocol or some study

STENT THROMBOSIS
v. imp entity came into lime light because of the concern raised by certain studies esp. with the use of DES. has high morbidity and mortality In one metaanalysis- 80 % presented with MI With 20% mortallty I Lets first know certain definitions

Time frame of ARC definitions of stent thrombosis

1 month 1 year

Early 1 mo

Late > 1 mo 1year

Very Late > 1year

Acute Subacute 1d >1d - 1mo 0 day to 1 day >1 day to 1 month >1 month to 1 year > 1 year
Cutlip D et al. Circulation. 2007;115:2344-2351

Acute stent thrombosis Subacute stent thrombosis Late stent thrombosis Very late stent thrombosis

Time frame of ARC definitions of stent thrombosis

1 month 1 year

Early 1 mo

Late > 1 mo 1year

Very Late > 1year

Acute Subacute 1d >1d - 1mo 0 day to 1 day >1 day to 1 month >1 month to 1 year > 1 year
Cutlip D et al. Circulation. 2007;115:2344-2351

Acute stent thrombosis Subacute stent thrombosis Late stent thrombosis Very late stent thrombosis

Patient/lesion factors in stent thrombosis

Premature discontinuation of dual antiplatelets Low EF Diabetes Renal insufficiency ACS Ostial and/or bifurcation In-stent restenosis lesions Delayed healing
Luscher T et al. Circulation. 2007;115:1051-1058. Holmes Jr et al. J Am Coll Cardiol. 2007;50:109-108.

Stent Thrombosis: A Multifactorial Problem

Lesion

Long lesions Small diameter Multivessel Acute myocardial infarction (AMI) Diabetes Bifurcations

Technical
Underexpansion Incomplete wall
apposition Crush technique Overlapping

Stent Thrombosis

Stent Patient

Antiplatelet noncompliance Response variability

Material Polymer matrix Antithrombotic

agent

Adapted from Kereiakes DJ et al. Rev Cardiovasc Med. 2004;5:9-15.

Mechanism of Stent Thrombosis After BMS complete endothelialization - by 3 - 4 months , hence ST occurs mostly in first 3 months & esp in first month . In DES delayed reendothelialization( upto years) and arterial healing compared with BMS, results in potentially thrombogenicity , hence potential for ST, hence the need for

Consequences of Stent Thrombosis

60% Nonfatal MI, , 24% Death

7% Unstable Angina

Stent Thrombosis: Clinical Outcomes

SES (n=13) Death (%) Myocardial infarction (%) Q-wave (%) NonQ-wave (%) 4 (31) 13 (100) 8 (62) 5 (39) BMS (n=15) 5 (33) 13 (87) 5 (33) 9 (60) PES (n=22) 7 (32) 17 (77) 7 (32) 10 (46) BMS (n=18) 5 (28) 14 (78) 5 (28) 10 (56)

Mauri L et al. N Engl J Med. 2007;356:1020-1029.

Stent Thrombosis: Cumulative Incidence

ARC Definition: Definite and Probable
SES Early (0-30 days) Late (31-360 days) Very late thrombosis* (361-1440 days) Any thrombosis (0-1440 days) 0.5% 0.1% 0.9% BMS 0.3% 1.0% 0.4% PES 0.5% 0.4% 0.9% BMS 0.5% 0.3% 0.6%

1.5%

1.7% LR P=.70

1.8%

1.4% LR P=.52

*Proportional hazards assumption not rejected. ARC=Academic Research Consortium; BMS=bare metal stent; LR=lesion revascularization; PES=paclitaxel-eluting stent; SES=sirolimus-eluting stent.
Mauri L et al. N Engl J Med. 2007;356:1020-1029. Pooled Data from RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS; Pooled Data from TAXUS 1 2 4 and 5.

Stent thrombosis
Cumulative risk of stent thrombosis %

Unadjusted
2

Stent type
BMS n=20 058 DES n=21 717

Total cohort N = 41 775 stents

0.5% per year

0 0 1 2

Time (years)

James ESC 2007

Conclusion

The incidence of stent thrombosis did not differ significantly between patients with DES and those with BMS with similar consequences in randomized clinical trials,

Kaplan-Meier Curves Representing the Estimated 4-Year Cumulative Incidence Rates of Stent Thrombosis, Death, Myocardial Infarction, and Target-Lesion Revascularization for the Pooled Randomized Trials of Sirolimus-Eluting Stents and Bare-Metal Stents

Stone GW et al. N Engl J Med 2007;356:998-1008

Conclusion
The use of sirolimus-eluting stents does not have a significant effect on overall long-term survival and survival free of myocardial infarction, as compared with bare-metal stents There is a sustained reduction in the need for reintervention after the use of sirolimus-eluting stents The risk of stent thrombosis is at least as great as that seen with bare-metal stents

Conclusion
Stent thrombosis after 1 year was more common with both sirolimus-eluting stents and paclitaxel-eluting stents than with bare-metal stents Both drug-eluting stents were associated with a marked reduction in target-lesion revascularization There were no significant differences in the cumulative rates of death or myocardial infarction at 4 years

Hazard Ratios for Death, Myocardial Infarction, or Reintervention and Kaplan-Meier Curves for Survival Free of Myocardial Infarction and Reintervention

Kastrati A et al. N Engl J Med 2007;356:1030-1039

Most important conclusions which can be drawn Up to 1 year after PCI (Ac ,S. A , & LATE PHASE)

Incidence and consequences of Stent thrombosis

same in BMS and DES.

After 9 months-1 year ,incidence of ST only slightly higher in DES group & even this difference does not translate into increased MACE as compared To BMS .(Kastrati A, Stone G W NEJM

Most important and common cause of ST

Premature stopping of clopidogrel( Basket Late trial)

The data on the two previously approved DES have demonstrated a significant reduction in the need for repeat revascularization vs BMS Recently the rare but catastrophic event of late stent thrombosis was shown to be increased with these DES compared to BMS However, any increased incidence of LST appears to be offset by a reduction in downstream revascularization events prevented by DES

In a registry of 6,906 patients who received BMS or DES, there was no difference in clinical outcomes or ST rate over 1 year of follow-up (17). In another registry of 8,146 patients who received DES between 2002 and 2005, a persistent excess ST risk of 0.6%/year was found compared with historical control subjects who received BMS (2). A meta-analysis of 8 trials in which 4,545 patients were randomized to sirolimuseluting stent (SES) or paclitaxel-eluting stent (PES) versus BMS revealed no difference in rates of ST over 4 years of follow-up (5). another meta-analysis of 14 randomized clinical trials, in which a total of 6,675 patients were randomized to either SES or PES versus BMS, confirmed a 0.5% excess risk of very late ST with DES

Factors Influencing DES Thrombosis

9-Month Cumulative Stent Thrombosis
29 Patients (%) 30

20 6.2 8.7

10

2.5

3.3

3.9

DES=drug-eluting stent.

Diabetes Unprotect. Bifurcation Renal left main 2 stents failure artery

Iakovou I et al. JAMA. 2005;293:2126-2130.

Prior Premature brachy- antiplatelet therapy therapy withdrawal

BASKET LATE Trial: Primary Composite End Point

Composite of Cardiac Death or Nonfatal MI (%)
6 5 4 3 2 1 0 DES
P=.01.
Pfisterer M et al. J Am Coll Cardiol. 2006;48:2584-2591.

4.9

1.3

In the year following clopidogrel discontinuation, the primary composite end point of cardiac death or MI occurred significantly more frequently in the DES group than in the BMS group (4.9% vs 1.3%, P=.01)

Patients (%)

BMS

therapy

Premature discontinuation of antiplatelet

the most important predictor of stent thrombosis after implantation* At 9 month follow-up, 29 patients had stent thrombosis (1.3%) Common reasons for discontinuation included Among the 29 patients, 13 died (case 41% Surgical procedures fatality rate 45%)
35% Intolerance to bleeding 24% Noncompliance

Prevention of ST Because of High mortality & morbidity associated with ST, it is imp for clinicians to stratify the individual pts risk for ST, restenosis, and bleeding when selecting strategies. appropriate revascularization

Specifically, if the patient is unlikely to comply with long-term clopidogrel therapy,

is likely to require surgery in the nearterm( within 1 year) or is at risk of bleeding, Alternative treatments are preferred, such as implanting BMS or doing plain balloon angioplasty performing bypass surgery, OR

Future Directions Innovation is needed to overcome the stent problems: stent thrombosis, restenosis

Different

coatings (e.g. pro-healing strategies)

New polymers Bioabsorbable stents New antiplatelet strategies (prolonged therapy?) New antiplatelet drugs (minimize drug resistance) More selective use of DES (avoid off-label)

Short-term Prevention

Secondary and LongTerm Prevention: PostPCI

Acute stent thrombosis Sub-acute stent thrombosis Late stent restenosis Major adverse cardiac events Other atherothrombotic events (all arterial beds) 24 hours incidence: 0.6% Days to weeks incidence: <5% Up to 12 months incidence: 15% First year incidence: ~20% Life-long

Long-term Prevention

Adjuvant Medical Treatment

Drug eluting stents PCI I year Life-long

ASPIRIN CLOPIDOGREL Loading Pretreatment

GP IIb/IIIa inhibitor UH / LMWH / bival

ASPIRIN CLOPIDOGREL BETA BLOCKERS STATINS ACE inhibitors Control of DM DIET

ASPIRIN BETA BLOCKERS STATINS ACE inhibitors DIET Control of DM ?CLOPIDOGREL

Mechanism of Benefits of Statin

Pleiotropic properties Stabilize plaquex Improve endothelial functionxx Inhibit platelet aggregationxxx Reduce inflammationxxxx

x xx xxx

xxxx

Keidar, Br J Clin Pharmacul 1994;38:513-519 Anderson, N Engl J. Med 1995; 332:438-493 Merten, Circulation 2001; 103:2032-2034 Notarbartolo, Arterioscter Thromb Vasc Biol 1995;15:247 Jialal, Circulation 2001;103:1933-1935 Strandberg, Lancet 1999; 353:118-119

LIPS Conclusions

LIPS: first prospective trial to demonstrate benefits of statin therapy (fluvastatin 80 mg/d) in patients post-first PCI ( stent) for reducing MACEs The risk of MACEs was significantly reduced by 22% over 4 years Fluvastatin 80 mg/d has an excellent safety profile, with no CPK elevations

Timing of stent thrombosis with BMS

(A) 10 8 6 n 4 2 0 (B) 0 Percent of patients 100 80 60 40 20 0 0 30 60 90 Days after PCI 120 600 30 60 Days after PCI 120 600
(A) incidence of stent thrombosis (n = number of stent thromboses per day) following bare-metal stent implantation. Acute and subacute stent thrombosis ( 30 days) are in yellow, late stent thrombosis (> 30 days) in yellow. (B) Cumulative incidence of stent thrombosis following bare-metal stent implantation. Wenaweser P et al. EHJ. 2005;26:1180-1187.

Conclusions The VerifyNow assay is a true point-of-care assay that can measure patient response to aspirin, clopidogrel and GP IIb/IIIa inhibitors. Aspirin non-responsiveness as measured by the VerifyNow assay appears to be associated with post-PCI myocardial infarction. Clopidogrel non-responsiveness as determined by the VerifyNow P2Y12 assay appears to be associated with thrombotic events after drug-eluting stent implantation. The GRAVITAS study will determine (1) whether increasing the maintenance dose overcomes non-responsiveness, and (2) whether tailoring the dose based on the VerifyNow assay improves clinical outcomes.

What are our targets ?

Long-term Post-PCI Management

Prevention of stent thrombosis Prevention of plaque rupture

Evidence for long-term antiplatelet therapy

What is the right dose of ASA Efficacy and safety of combined therapy

Proven therapies and issues with compliance medical therapy Therapies on horizon

At what level can we have the greatest impact?

Interventions-Revascularization-DevicesProcedures Specialist/Cardiologist-Invasive Dx/TxMonitoring/Rehab/Reinforcement

4 2 & 3 1 & 2 Primary Care Physician

Risk Stratification-Rx Optimization/ Adherence-FD & Specialist Recognition-Screening-Initial Therapy- Family MD Community Based Awareness/Understanding

Prevention Awareness Programs/PHN

Reduction Cocktail for 2 Prevention ASA (Plavix post

ACS/PCI) Lipid Targets TC 4.5, TG 1.7, HDL 1.2, LDL 2.0 (1.8) TC/HDL < 4 (3) ACE inhibitor Ramipril 2.5 10 mg Perindopril 2 mg 8 Trandolapril 1 mg 4 Beta-blocker for postMI or LV dysfunction

Lipid management: (TG less than 200 mg per dL Primary goal LDL-C substantially less than 100 mg per dL (optional target less than 70 mg per dL for very-high-risk patients) Primary goal :NonHDL-C substantially less than 130 mg per dL

Summary of ESC, British, and US Guidelines for Lipid Management LDL-C remains primary treatment target Established goals for patients at highest risk ESC: <2.5 mmol/L (97 mg/dl) British: <2 mmol/L (77 mg/dl) US: <1.8 mmol/L (70 mg/dl) HDL-C not currently a treatment target <1.03 mmol/L (men) and <1.3 mmol/L (women) considered marker of increased risk Triglycerides are not currently a treatment target >1.7 mmol/L considered a marker of metabolic syndrome

Physical activity Minimum goal 30 minutes of activity 5 days per week; optimal daily
brisk walking, jogging, cycling, or other aerobic activity like swimming

Assess risk, preferably with exercise test, to guide prescription

Potential Cumulative Impact of 2 Prevention Treatments

RRR
None ASA

If Event Rate
8% 6%

If Event Rate
16% 12%

-Blockers 4.5% 9.0% Lipid 30% 3.0% 6.0% lowering ACE25% 2.3% 4.6% inhibitors Cardiac 25% 1.7% 3.4% Rehab CUMULATIVE BENEFITS ARE LIKELY TO BE IN EXCESS OF
Adapted from Yusuf, S. Two decades of progress in preventing vascular disease. Lancet 2002; 360: 2-3.

25% 25%

78% RRR, WHICH IS SUBSTANTIAL

Class I 1. After PCI, use of aspirin should be continued indefinitely. (Level of Evidence: A) 2. The duration of P2Y12 inhibitor therapy after stent implantation a. In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include
clopidogrel 75 mg daily,570 prasugrel 10 mg daily,567 and ticagrelor 90 mg twice daily.568 (Level of Evidence: B) b. In patients receiving DES for a non-ACS indication, clopidogrel 75 mg daily should be given for at least 12 months if the patient is not at high risk of bleeding.208,212,571 (Level of Evidence: B) c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks).572 (Level of Evidence: B)

Antiplatelet Therapy
.

After PCI, in patients without allergy or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least 1 month after BMS, 3 months after sirolimus-eluting stent, 6 months after paclitaxel-eluting stent, after which daily long-term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg.

MODIFIED

Antiplatelet Therapy
Aspirin.
After PCI, in patients without allergy or increased risk of bleeding, aspirin 162 mg to 325 mg daily at least 1 month after BMS, 3-6 months after DES then, continued indefinitely at a dose of 75 mg to 162 mg /day

Antiplatelet Therapy
CLOPIDOGREL
I IIa IIb III

DES

clopidogrel 75 mg daily(or prasugrel 10 mg Daily or ticagrelor 90 mg twice daily) should be given for at least 12 months if not at high risk of bleeding. Continuation of clopidogrel therapy beyond 1 year may

I IIa IIb III

Antiplatelet Therapy- Cont. Clopidogrel

If BMS is used
- for Non ACS cases- minimum of 1 month& ideally up to 12 months (unless at increased risk of bleeding; then it should be given for two weeks). For ACS cases- given for upto 1 yr unless at increased risk of bleeding; then it should be given for two weeks).

COGENT (Clopidogrel and the Optimization of GI Events) trial randomized pts with DAPT to clopidogrel and omeprazole or clopidogrel and placebo, no difference in CV events between the 2 groups, GI events were halved in omeprazole group. Carefully evaluate the indication for PPI therapy in pts treated with clopidogrel, based on the presence or absence of the risk factors . The need for GI Protection of risk factors for bleeding.

with the number

Prior upper GI bleeding is the strongest and most consistent risk factor for GI bleeding on antiplatelet therapy. Patients with ACS and prior upper GI bleeding are at substantial cardiovascular risk, so DAPT with concomitant use of a PPI may provide the optimal balance of risk and benefit.

Rockall score to identify patients at risk of adverse outcome following acute upper gastrointestinal bleeding. variable Age Shock Score 0 <60 nil Score 1 60-79 HR< 100 SBP>100 Score 2 >80 SBP <100 CHF,IHD Major morbity Renal failure,liver Failure, metastases Score 3

Co morbidity nil

Diagnosis

Mallory weiss

All other diag GI malignancy

e/o bleeding none

Blood,adherent clot A score less than 3 carries good prognosis Spurting vessel but total score more than 8 carries high risk of mortality

A Reminder of the Significance of Stent Thrombosis ST typically presents as a large MI, with high rates of subsequent mortality (and also recurrence!) A Reminder of the Significance of Stent Thrombosis ST typically presents as a large MI, with high rates of subsequent mortality (and also recurrence!)

Antiplatelet Therapy

I IIa IIb III

I IIa IIb III

For all post-PCI stented patients receiving a DES, clopidogrel 75 mg MODIFIED daily should be given for at least 12 months if not at high risk of bleeding. For post-PCI patients receiving BMS, MODIFIED clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless at increased risk of bleeding; then it should be given for two weeks).

Antiplatelet Therapy
I IIa IIb III IIb III
If clopidogrel is given at the time of procedure, supplementation with GP IIb/IIIa receptor antagonists can be beneficial. I IIa IIb III For patients with an absolute contraindication to aspirin, it is reasonable to give a 300 mg to 600 mg loading dose of clopidogrel, administered at least 6 hours before PCI, and/or GP IIb/IIIa antagonists at the time of PCI. In patients for whom the physician is concerned about risk of bleeding, a lower dose of 75 mg to 162 mg of aspirin is reasonable during the initial period after stent implantation.
NEW

I IIa IIb III

I IIa IIb III

NEW

Continuation of clopidogrel therapy beyond 1 year may be considered in patients undergoing DES placement.

Drug-Eluting and Bare-Metal Stents

I IIa IIb III
MODIFIED A DES should be considered as an alternative to a BMS in patients for whom clinical trials indicate a favorable effectiveness/safety profile.

I IIa IIb III

Before implanting a DES, the interventional cardiologist should discuss with the patient the need for and duration of DAT (dual antiplatelet therapy) and confirm the patients ability to comply with the recommended therapy for DES.

NEW

I IIa IIb III

NEW In patients undergoing preparation for PCI and who are likely to require invasive or surgical procedures for which DAT must be interrupted during the next 12 months, consideration should be given to implantation of a BMS or performance of balloon angioplasty with provisional stent implantation instead of the routine use of a DES.

Drug-Eluting and Bare-Metal Stents

I IIa IIb III
NEW In patients for whom the physician is concerned about risk of bleeding, a lower dose of 75 mg to 162 mg of aspirin is reasonable .

I IIa IIb III

A DES may be considered for clinical and anatomic settings in which the effectiveness/safety profile appears favorable but has not been fully confirmed by clinical trials.

MODIFIED

Secondary Prevention
I

IIa

Ask, advise, assess, and assist patients to stop smoking Clopidogrel 75 mg daily:

PCI I (B) no PCI IIa (C)

I
I I IIa

Statin goal:

LDL-C < 100 mg/dL I (A) consider LDL-C < 70 mg/dL IIa (A)

Daily physical activity 30 min 7 d/wk, minimum 5 d/wk I (B) Annual influenza immunization I (B)

Secondary Prevention and Long Term Management

Goals
I

Smoking 2007 Goal:

Complete I cessation. No exposure to environmental I tobacco smoke.

I

Class I Recommendations Status of tobacco use should be asked at every visit. Every tobacco user and family member MODIFIED who smoke should be advised to quit at every visit. The tobacco users willingness to quit should be assessed. The tobacco user should be assisted by counseling and developing a plan for quitting. Follow-up, referral to special programs, or pharmacotherapy (including nicotine replacement and pharmacological rx) should be arranged. Exposure to environmental tobacco smoke at home and work should be

Secondary Prevention and Long Term Management

Goals Blood pressure control:
2007 Goal: < 140/90 mm Hg or <130/80 mm Hg if chronic kidney disease or diabetes
I

For patients with blood pressure 140/90 mm Hg (or 130/80 mm Hg for patients with chronic kidney disease or diabetes): It is recommended to initiate or maintain lifestyle modification (weight control, physical activity, alcohol moderation, sodium , and emphasis on consumption of fresh fruits, vegetables, and low-fat dairy products).
MODIFIED

Class I Recommendations

It is useful as tolerated, to add blood pressure medication, treating initially with beta-blockers and/or ACE inhibitors, with the addition of other drugs such as thiazides as needed to achieve goal BP.

Secondary Prevention and Long Term Management

Goals
Lipid management: 2007 goal: LDL-C << than 100 mg/dL (if TG 200 mg/dL, non HDL-C < 130 mg/dL
I

Recommendations
Starting dietary therapy in all patients MODIFIED is recommended. intake of sat. fats (< 7% of total calories), trans fatty acids and cholesterol (< 200 mg/d). Adding plant stanol/sterols (2 g/d) and/or viscous fiber (> 10 g/d) is reasonable to further lower LDL-C.
NEW

IIa

Promotion of daily physical activity and MODIFIED weight management is recommended. consumption of omega-3 fatty acids in the form of fish or in capsule form (1 g/d) for risk reduction. For treatment of elevated TG, higher doses are usually necessary for risk reduction.

IIb It may be reasonable to encourage

Substantial Risk of CHD Events Remains for Many Patients on Statin Therapy PROSPER*** (5804) Pravastatin 40 mg 24% 76% HPS*** (20,536) Simvastatin 40 mg 27% 73% LIPID*** (9014) Pravastatin 40 mg 24% 76% CARE*** (4159) Pravastatin 40 mg 24% 76% 4S** (4444) Simvastatin 20 mg 26% 74% ASCOT-LLA** (10,305) Atorvastatin 10 mg 38% 62% AFCAPS/TexCAPS** (6605) Lovastatin 20 or 40 mg 40% 60% WOSCOPS** (6595) Pravastatin 40 mg 31% 69% Remaining risk Risk reduction Trial (N) Statin treatment vs. placebo Clinical events* *Nonfatal myocardial

Secondary Prevention and Long Term LDL-C should be < 100 mg/dL. Management
Goals
Lipid management: 2007 goal: LDL-C << than 100 mg/dL (if TG 200 mg/dL, non HDL-C < 130 mg/dL

Recommendations Further reduction to < 70 mg /dL is reasonable. MODIFIED If baseline LDL-C is 100 mg/dL, LDL-lowering drug rx should be initiated. MODIFIED If on-treatment LDL-C is 100 mg/dL intensify LDL-lowering drug rx (may require LDLNEW

lowering combination is recommended

Secondary Prevention and Long Term Management

Goals
Lipid managemen t: (TG 200 mg/dL or greater) Primary goal: NonHDL-C < 130 mg/dL
I

Recommendations
A fasting lipid profile should be assessed in all MODIFIED If TG are 150 mg per dL or HDL-C < 40 mg per dL, weight management, physical activity, and smoking cessation should be emphasized.
MODIFIED

If TGs are 200 to 499 mg per dL, nonHDL-C target should be less than 130 mg per dL.
MODIFIED

If TGs are 200 to 499 mg/dL, nonHDL-C target is < 130 mg/dL. (Class I; LOE: B); further I IIa
NEW

reduction of nonHDL-C to < 100 mg dL is reasonable. (Class IIa; LOE: B)

Secondary Prevention and Long Term Management Therapeutic options to reduce nonHDL-C
Goals
Lipid managemen I t: (TG 200 IIa mg/dL or greater) Primary goal: IIa NonHDL-C < 130 mg/dL
I

include:

Recommendations

More intense LDL-C-lowering rx is indicated Niacin (after LDL-C-lowering rx) can be beneficial MODIFIED Fibrate therapy (after LDL-C-lowering rx) MODIFIED can be beneficial If TG are 500 mg/dL, therapeutic options indicated and useful to prevent pancreatitis are fibrate or niacin before LDL-lowering rx; and treat LDL-C to goal after TG-lowering rx. Achieving non
MODIFIED NEW

Secondary Prevention and Long Term Management

Goals
Physical activity: 2007 Goal: 30 min 7 d per wk; minimum 5 d per wk
I

Recommendations
For all patients, it is recommended that riskMODIFIED be assessed with a physical activity history and/or an exercise test to guide prescription. For all patients, encouraging 30 to 60 min of MODIFIED moderate-intensity aerobic activity, such as brisk walking, on most, preferably all, days of the week, supplemented by an increase in daily lifestyle activities (e.g., walking breaks at work, gardening, household work). Advising medically supervised programs (cardiac rehabilitation) for high-risk patients (e.g., recent acute coronary syndrome or revascularization, HF) is recommended.
MODIFIED

IIb

Encouraging resistance training 2 d per week NO CHANGE may be reasonable.

Secondary Prevention and Long Term Management

Goals Weight management: Goal: BMI 18.5 to 24.9 kg/m2
It is Class I Recommendationsindex useful to assess body mass and/or waist circumference on each visit and MODIFIED I consistently encourage weight maintenance/reduction through an appropriate balance of physical activity, caloric intake, and formal behavioral programs when indicated to maintain/achieve a body mass index between 18.5 and 24.9 kg/m2.

Waist The initial goal of weight loss therapy should be MODIFIED circumference: I to reduce body weight by approximately 10% Women: < 35 in. from baseline. With success, further weight (102 cm) loss can be attempted if indicated through Men: < 40 in. (89 further assessment. cm)

I If waist circumference (measured horizontally at

the iliac crest) is 35 inches (89 cm)MODIFIED in women and 40 inches (102 cm) in men, it is useful to initiate lifestyle changes and consider treatment strategies for metabolic syndrome as indicated.

Secondary Prevention and Long Term Management

Goals Diabetes manageme nt: Goal: HbA1c < 7%
I

Class I Recommendations
It is recommended to initiate lifestyle and pharmacotherapy to achieve near- MODIFIED normal HbA1c. Beginning vigorous modification of other risk factors (e.g., physical MODIFIED activity, weight management, BP control, and cholesterol management as recommended above) is beneficial. Coordination of diabetic care withNEW patients primary care physician or endocrinologist is beneficial.

Secondary Prevention and Long Term Management

Goals Antiplatelet agents/ anticoagulant s: Aspirin
I

Class I Recommendations
For all post-PCI stented patients MODIFIED without aspirin resistance, allergy, or increased risk of bleeding, aspirin 162 to 325 mg daily should be given for at least 1 month after bare-metal stent implantation, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which longterm aspirin use should be continued indefinitely at a dose of 75 to 162 mg daily.

Secondary Prevention and Long Term Management

Goals Antiplatelet agents/ anticoagulant s: Aspirin
IIa

Recommendations In patients where the physician is concerned about the risk of bleeding lower-dose 75 to 162 mg of aspirin is reasonable during the initial period after stent implantation.
NEW

For all post-PCI patients who receive a Goals Class I Recommendations clopidogrel drug-eluting stent (DES), 75 mg I daily should be given for at least 12 Antiplatelet months if patients are not at high agents/ risk of anticoagulant bleeding.

Secondary Prevention and Long Term Management

s: Clopidogrel

For post-PCI patients receiving a bare metal stent (BMS), clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient MODIFIED of bleeding; then is at increased riskRECS it

Secondary Prevention and Long Term Management

Goals Antiplatelet agents/ anticoagulant s: Clopidogrel
I

Recommendations For all post-PCI non-stented STEMI

patients, treatment with clopidogrel should continue for at least 14 d. Long-term maintenance therapy (e.g., 1 year) with clopidogrel (75 mg per day orally) is reasonable in STEMI and nonSTEMI patients who undergo PCI without reperfusionNEW RECS therapy.

IIa

Goals

Secondary Prevention and Long Term Management

Class I Recommendations
MODIFIED

Antiplatelet agents/ anticoagulant s: Warfarin

Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with increased risk of bleeding and should be monitored NEW closely. In patients requiring warfarin, clopidogrel, and aspirin therapy after PCI, an INR of 2 to 2.5 is recommended with low dose aspirin (75 to 81 mg) NEW and a 75 mg dose of clopidogrel.

Secondary Prevention and Long Term Management

Goals
ACE Inhibitors
I

ACE inhibitors should be started and Recommendations in all patients with LVEF continued indefinitely 40% and for those with hypertension, diabetes, or chronic kidney disease, unless contraindicated. MODIFIED ACE inhibitors should be started and MODIFIED continued indefinitely in patients who are not lower risk (lower risk defined as those with normal LVEF in whom cardiovascular risk factors are well controlled and revascularization has been performed), unless MODIFIED contraindicated. Among lower risk patients (i.e., those with normal LVEF in whom cardiovascular risk factors are well controlled and revascularization has been

IIa

Secondary Prevention and Long Term Management

Goals
ReninAngiotensi nAldosteron e System Blockers: ARBs
I

Recommendations
MODIFIED Use of ARBs is recommended in patients who are intolerant of ACE inhibitors and have HF or have had an MI with LVEF 40%.

ARBs are useful in other patients who are ACE-inhibitor intolerant and have hypertension.

NEW

IIb

NEW Considering use in combination with ACE inhibitors in systolic dysfunction HF may be reasonable.

Secondary Prevention and Long Term Management

Goals
ReninAngiotensi I nAldosteron e System Blockers: Aldosteron e Blockade

Class I Recommendations Use of aldosterone blockade in post-MI patients without significant renal dysfunction or hyperkalemia is recommended in patients who are already receiving therapeutic doses of an ACE inhibitor and beta blocker, have an LVEF of 40% and have either diabetes or HF.
MODIFIED

Secondary Prevention and Long Term Management

Goals
ReninAngiotensi I nAldosteron e System Blockers: Aldosteron e Blockade

Class I Recommendations Use of aldosterone blockade in post-MI patients without significant renal dysfunction or hyperkalemia is recommended in patients who are already receiving therapeutic doses of an ACE inhibitor and beta blocker, have an LVEF of 40% and have either diabetes or HF.
MODIFIED

Secondary Prevention and Long Term Management

Goals

BetaBlockers

It is beneficial to start and continue Class I Recommendations betablocker therapy indefinitely in all patients I who have had MI, acute coronary syndrome, or left ventricular dysfunction with or without HF symptoms, unless contraindicated. It is reasonable to consider longterm therapy for all other patients with coronary or other vascular disease MODIFIED RECS or diabetes unless contraindicated.

IIa

Secondary Prevention and Long Term Management

Goals Influenza Vaccination
I

Class I Recommendations

Patients with cardiovascular disease should have an annual influenza vaccination.

NEW

Post PCI Pt needing non cardiac surgery There are 2 fundamental questions that each clinician must ask: 1 Is stopping DAPT pharmacotherapy in the

periprocedural period necessary? This question is particularly relevant in first month post PCI. 2 If DAPT IS interrupted,

what is the optimal timing and duration for temporary

A Practical Approach to Managing Cardiovascular Risk and Bleeding Complications Avoid cessation of all antiplatelet therapies after PCIwhen possible. Avoid cessation of clopidogrel (even when aspirin is continued) within the first 30 days after PCI and either DES or BMS placement when possible. Defer elective endoscopic procedures, possibly up to 12 months, if clinically acceptable from the time of PCI with DES . Perform endoscopic procedures, particularly those associated with bleeding risk, 57 days after thienopyridine drug cessation. Aspirin should be continued when possible. Resume thienopyridine and aspirin drug therapy after the procedure once hemostasis is achieved. Continue platelet-directed therapy in patients undergoing elective endoscopy procedures associated with a low risk for bleeding.

Practical approach to minimizing CV risk Cessation of all antiplatelet therapies after PCI, at any time, for any stent, is associated with an increased risk of thrombotic events, including late stent thrombosis esp within 7 to 30 days of drug discontinuation. Cessation of clopidogrel (alone) during the early period after

Suggested Management of Patients with Cardiac Stents who require Non Cardiac Surgery*
Bare Stent Drug Stent 1st 3 months

Tx
ONLY EMERGENCY SURGERY Continue aspirin during Sx if at all possible. Significant (>10%) risk of major MI if aspirin and clopidogrel ceased. ELECTIVE SURGERY FEASIBLE BUT AVOID IF POSSIBLE. Can temporarily cease clopidogrel at low risk if aspirin continued. Surgery should be done on aspirin. Very low risk with Bare stent even if all drugs ceased. Probable 0.2-0.5% risk of 0.2event in Drug Stents if all antiplatelet agents ceased.

Highest Risk Medium Risk Lowest risk

1st month

1-6 months

3-12 months

> 6 months

> 12 months

* This is a complex field with rapidly changing data. These guidelines were accepted by the Medical Advisory Committee of Eastern and Sutherland Heart Clinics in 12/2007 and may be revised from time to time. T he risks of each patient may vary depending upon length, diameter and position of stent but the above form the usual recommendations. Where possib le, discussion with the usual Cardiologist is always recommended.

ELECTIVE

POST PCI Needing Sx Days from PCI

Emergency
Go for it- ct Asp if possible 10% risk of MI if both stopped

< 1 Month Defer Sx for Atleast 1month

1-6 Months

> 6 Months

Type of Stent

BMS Stop Clop for a week Ct Aspirin Restart Clop post Sx

DES Defer Sx for > 6 months

BMS/DES Stop Clop for a week Ct Aspirin Restart Clop post Sx

ELECTIVE

POST PCI Needing Sx Days from PCI

Emergency
Go for it- ct Asp if possible 10% risk of MI if both stopped

< 1 Month Defer Sx for Atleast 1month

1-6 Months

> 6 Months

Type of Stent

BMS Stop Clop for a week Ct Aspirin Restart Clop post Sx

DES Defer Sx for > 6 months

BMS/DES Stop Clop for a week Ct Aspirin Restart Clop post Sx

Risk of GI BLEED WITH DAPT is significant about 2% and as high as 12% in high-risk pts with prior peptic ulcer bleeding. GI bleed after PCI associated with increased morbidity, mortality, duration of hospitalization and cost. RISK FACTORS Advanced age a history of peptic ulcer disease, co-administration of NSAIDc, co-administration of anticoagulants, CRF,DM ,Liver disease and physiological stress,

OASIS and CURE close relation between major bleeding and subsequent MI, stroke and death at 30 days; 10% of patients who got 2 or more units of BT died within 30 days vs 2.5% of those who did not sustain a bleed. Why -pts who with hemrgic complications are frequently older, with significant comorbidities such as renal insufficiency. Therefore, bleeding may be a marker of a sicker patient, which confers an increased risk of death

Aspirin monotherapy Aspirin leads to suppression of mucosal prostaglandin synthesis and subsequent formation of mucosal erosions. Whereas the inhibition of thromboxane-A2-mediated platelet function is dose independent (at least for daily doses N30 mg), the impairment of PGE2-mediated cytoprotection in the GI mucosa is dose dependent [14]. Aspirin amplifies the risk of bleeding by causing new mucosal lesions or aggravating existing ones, which are associated with a greater relative risk (four- to sixfold) at the higher doses of aspirin [14]. Of patients with a history of peptic ulcer bleeding who continue to take aspirin after ulcer healing and eradication of Helicobacter pylori infection, up to 15% experience recurrent bleeding within a year [15]. 4.2. Clopidogrel monotherapy Whether clopidogrel causes mucosal injury and bleeding from preexisting mucosal lesions is uncertain. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events trial, GI hemorrhage (0.52% vs. 0.72%, Pb .05) was

4.2. Clopidogrel monotherapy Whether clopidogrel causes mucosal injury and bleeding from preexisting mucosal lesions is uncertain. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events trial, GI hemorrhage (0.52% vs. 0.72%, Pb .05) was significantly less frequent with clopidogrel compared with aspirin [16]. Available evidence suggests that clopidogrel does not induce new ulcer formation but may cause rebleeding due to impaired hemostasis only in subjects with underlying mucosal defects or scarring [17]. In randomized controlled trials, among patients with acute coronary syndrome (ACS), the addition of clopidogrel to aspirin appears to increase the relative risk of all hemorrhagic events by 50% [18]. However, it must be remembered that the patients

The risk of adverse GI events depends on the dose and duration of antiplatelet therapy. CURE study- the risk of GI bleeding with combination clopidogrel (75 mg) with high-dose aspirin (N200 mg) was significantly greater than that with low dose aspirin (100 mg) (3% vs. 4.9%, P=.0009 APT. So what to do in a pt with GI BLEED

Therefore, the discontinuance of DAPT- risk and the initiation of blood transfusion- risk as part of the treatment of post-PCI hemorrhage need to be thoroughly analyzed on an individual basis. decision to administer BT to a patient should not be based on a hemoglobin level but rather on a pt's symptoms and on the risk of ischemic complications from acute anemia such as angina,CHF Hypotension etc patient's risk is defined as the presence of unrevascularized coronary artery territory, valvular heart disease and congestive heart failure Judicious transfusion should be given for hemodynamically significant blood loss.

Rockall score to identify patients at risk of adverse outcome following acute upper gastrointestinal bleeding. variable Age Shock Score 0 <60 Nil HR< 100 SBP>100 Score 1 60-79 Tachycardia HR> 100 SBP>100 Score 2 >80 Hypotension SBP <100 HR>100 CHF,IHD Major morbidly Renal failure, liver Failure, metastases Score 3

Co morbidity nil

Diagnosis

Mallory weiss

All other diag GI malignancy

e/o bleeding none

Blood in upper GI, adherent clot A score less than 3 carries good prognosis Spurting vessel but total score more than 8 carries high risk of mortality

Pt with GI Bleed

Give BT esp if Hb <8 gms%

Start or ct PPI Start PPI Features of High Risk Of Mortality Assess for hold antiplatelet for 24 hrs Massive Hemmorrhage or shock Hemodynamic stabilityand therapeutic upper GI Diagnostic & /or endoscopy within 24 hrs of e/o myocardial ischemia or CCF admission Assess risk of ST asso. With Ceassation of APT Assess risk continued GI bleed

Low risk of recurrent Bleed(Rockall score <5) Continue DAPT

High risk of recurrent bleed(Rockall score>5 Stop Aspirin, ct Clopi Plan to restart Aspirin in 2 wks

Continued GI Bleed Stop both Asp and clopi Aim to restart clopidogrel In 1-2 weeks

Pt with GI Bleed High risk features Massive Hrrage or shock &/or e/o myo. Ischemia or CCF Esp if Hb < 8 Start or ct PPI Assess hemod stability

Assess risk of ST asso. With Ceassation of APT vs risk of continued GI bleed

BT- Packed cells. Hold antiplatelets for 24 hrs Diagnostic and therapeutic Endoscopy within 12-24 hrs

Low risk of recurrent Bleed(Rockall score <5) Continue DAPT

High risk of recurrent bleed(Rockall score>5 Stop Aspirin, ct Clopi Plan to restart Aspirin in 1 wk

Continued GI Bleed or pt Nedding Sx Stop both Asp and clopi Aim to restart clopidogrel In 1 week & later aspirin

ScoreVariable0123Age (years)<60 607980Shock No shock (systolic BP >100, pulse <100) Tachycardia (systolic BP >100, pulse >100) Hypotension (systolic BP <100, pulse >100) Co-morbidityNil majorCardiac failure, ischaemic heart disease, any major co-morbidity Renal failure, liver failure, disseminated malignancyDiagnosisMallory Weiss tear, no lesion a SRH: stigmata of recent haemorrhage.

THANK YOU

Smoking: Goal smoke. Complete cessation

Ask about tobacco status at every visit. Strongly encourage patient and family to stop smoking and to avoid environmental tobacco

n summary, there appears to be no difference between BMS and DES in mortality or MI rates and no difference in stent thrombosis risk The major advantage of DES over BMS is a small reduction in TVR rates. Given cost considerations, it could be argued that selective use of DES to prevent restenosis and TVR in high-risk patients (i.e., patients with diabetes) and in high-risk lesions (longer and smaller-diameter stents) could be recommended (118), as it has been for elective PCI. The greatest challenge in selecting patients for DES implantation, however, is determining in an emergency situation whether the patient is a candidate for prolonged thienopyridine therapy. As with elective procedures, DES should be avoided in the presence of financial barriers to continuing prolonged dual-antiplatelet therapy, social barriers that may limit patient compliance, or medical issues that involve bleeding risks or the need for invasive or surgical procedures in the following year that would interrupt antiplatelet therapy.

Blood pressure control: Goal Less than 140 over 90 mm Hg or less than 130 over 80 mm Hg if chronic kidney disease or diabetes is present

restenosis, development of progressive disease in the same or a different coronary territory increased myocardial demand from various causes.

increased myocardial demand can result from the development of anaemia or aortic stenosis

In the BMS era, ST usually presented acutely or sub acutely, before neointimal formation.. In randomized trials that compared BMS with DES, rates of acute and sub acute ST among patients receiving dual antiplatelet therapy were similar for both stent types (1%)

Acute and subacute thrombosis of both BMS and DES have adverse clinical consequences. In a registry of patients who underwent DES implantation with 9-month follow-up, 24% of ST cases presented as death, 60% as nonfatal MI, and 7% as unstable angina. The case fatality rate for ST in this registry was 45%.

DES reduce restenosis. by inhibiting vascular smooth muscle migration and proliferation (green arrows). However, the drugs also inhibit reendothelialization, induce tissue factor (TF), and may prevent homing and proliferation of endothelial progenitor cells (EPCs; red arrows/bars).

However, in recent meta-analyses of DES trials, modest increases in rates of late and very late ST compared with BMS did not translate into a worse clinical outcome (3,10). These differences might reflect selection bias stemming from different diagnostic criteria for ST or possibly from implantation of DES in small vessels subtending limited myocardial territory. Stone G W , Kastrati A NEJM 2007

Late BMS thrombosis is an uncommon event (12) This is because of endothelialization of the stent which is Almost complete by 1 month of PCI

implantation in a patient dying of a non-DESrelated cause.52 It has been proposed that bone marrowderived endothelial progenitor cells may also be involved in reendothelialization.53,54 Interestingly, rapamycin inhibits proliferation, migration, and differentiation of human endothelial progenitor cells in vitro.55,56 Hence, drugs loaded on DES may affect the number as well as the homing and proliferation of endothelial progenitor cells, thus further preventing proper endothelial healing (Figure 2).

Impaired Reendothelialization Reendothelialization occurs after vascular injury and similarly after stent placement. Traditionally, it was believed that endothelial cells proliferate and migrate from intact neighboring coronary segments, eventually leading to the reendothelialization of the injured segment. In vitro, rapamycin and paclitaxel not only inhibit proliferation and migration of vascular smooth muscle cells but equally suppress endothelial cells,7,35,36,38,4951 thereby potentially impeding reendothelialization (Figure 2).

DES reduce neointima formation but may increase stent thrombogenicity Effect of sirolimus-eluting/ paclitaxel-eluting stent strut on the loca vessel wall after implantation. Sirolimus paclitaxel reduces neointima formation by inhibiting vascular smooth muscle migration and proliferation (green arrows). However, the drugs also inhibi reendothelialization, induce tissue facto (TF), and may prevent homing and prol of endothelial progenitor cells (EPCs; red arrows/bars).

988 CONSECUTIVE (non-selected) patients randomized 2:1 DES:BMS 746 patients alive without MACE 6 months after coronary stenting; CLOPIDOGREL stopped:BMS Vision stent, Guidant Corp: 281 SES: 264 PES: 281 Clopidogrel stopped at 6 months and then followed for another 12 months

Stent Thrombosis: A Multifactorial Problem

Lesion

Long lesions Small diameter Multivessel Acute myocardial infarction (AMI) Diabetes Bifurcations

Technical
Underexpansion Incomplete wall
apposition Crush technique Overlapping

Stent Thrombosis

Stent Patient

Antiplatelet noncompliance Response variability

Material Polymer matrix Antithrombotic

agent

Adapted from Kereiakes DJ et al. Rev Cardiovasc Med. 2004;5:9-15.

Technical Smaller final lumen diameter Underexpansion Incomplete wall apposition Stent length Crush technique Overlapping and multiple stents Persistent slow coronary blood flow

Patient related factors Antiplatelet noncompliance Response variability low ejection fraction diabetes mellitus,28 advanced age and stenting in the setting of an acute coronary syndrome.

Lesion characteritics Long lesions Small diameter vessel , 2.5 mm Multivessel disease Acute myocardial infarction (AMI) Diabetes Bifurcation lesion

Stent design platelet activationwas greater during the 30 days after implantation of an open-cell versus a closed-cell stent Stent Material Polymer matrix nonerodable polymers of the Cypher and Taxus DES provoke chronic eosinophilic infiltration of the arterial wall, suggestive of hypersensitivity reactions in a small number of cases Antithrombotic agent

increased risk in patients with acute coronary syndrome could be due to delayed healing, lack of endothelialization, and presence of a pronounced inflammatory and thrombogenic environment of the exposed necrotic core to flowing blood, accompanied by enhanced platelet reactivity; furthermore, rapamycin and paclitaxel potentiate thrombin-induced expression of tissue factor

Thrombogenicity of the Stent A predisposition for the development of stent thrombosis has been observed with certain stent materials; for example, platelet activation was greater during the 30 days after implantation of an open-cell versus a closed-cell stent.33 Stent strut thickness and polymer type and thickness also play an important role. It has been reported previously that the nonerodable polymers of the Cypher and Taxus DES provoke chronic eosinophilic infiltration of the arterial wall, suggestive of hypersensitivity reactions in a small number of cases

Furthermore, drugs loaded on DES may exert a prothrombogenic effect. Rapamycin (sirolimus), a macrocyclic lactone, is used on DES, because it is known to inhibit proliferation and migration of vascular smooth muscle cells, important factors in the development of neointima formation and restenosis, through interference with cell cycle regulators. 35,36 On a subcellular level, rapamycin binds to the FK-binding protein 12 and subsequently inhibits the mammalian target of rapamycin. The mammalian target of rapamycin is a downstream target of the phosphatidylinositol-3 kinase pathway, which in turn is involved in an inhibitory fashion in the regulation of tissue factor in endothelial cells and monocytes.3739 As a result, rapamycin inhibition of the mammalian target of rapamycin increases both thrombin- and tumor necrosis factor-induced endothelial tissue factor expression and activity at concentrations of rapamycin that are encountered in vivo (Figure 1).38,40

Paclitaxel is a lipophilic diterpenoid that binds to the -subunit of the tubulin heterodimer, promoting tubulin polymerization, cell cycle arrest, and, eventually, inhibition of vascular smooth muscle cell migration and proliferation. 41,42 In addition, paclitaxel is known to activate c-Jun NH2-terminal kinase,43,44 an important mediator of endothelial and monocytic tissue factor induction.37,39,45 Consequently, paclitaxel also enhances tissue factor expression and activity in endothelial cells44

In sirolimus-eluting stents, 80% of the rapamycin has eluted by 30 days, whereas paclitaxel-eluting stents have a biphasic drug release profile in vitro with an initial burst during the first 48 hours after implantation followed by a sustained low-level release for at least 2 weeks.

Thus, both rapamycin- and paclitaxel-induced tissue factor expression may contribute to a prothrombotic environment after deployment of DES, particularly in the acute and subacute setting and possibly in late stent thrombosis (Figure 1).

PREMIER Registry of 500 Patients With AMI and DES 1 in 7 Patients (13%) Stopped Clopidogrel Within 30 Days
15
Continued

Mortality (%)

10

Discontinued

0
0
No. at Risk Continue P<.001. Discontinued 431 68 431 68

9 10 11 12

Months
431 67 431 66 430 65 429 65 420 62

Spertus JA et al. Circulation. 2006;113:2803-2809.

Angioplasty in the setting of acute coronary syndromes could theoretically predispose to ST owing to the large thrombotic burden already present, suboptimal stent expansion to avoid the risk of no-reflow, or DES implantation on a thrombus that eventually disappears leading to malapposition. An SES registry reported increased risk of ST in patients who presented with acute coronary syndromes (28). However, 3 randomized trials comparing BMS and DES for primary angioplasty in acute MI found no difference in ST rate between the stent types (2931). Some registry reports have suggested increased ST rates in diabetic patients and patients with renal failure

Optimization of stent deployment (62) and dual antiplatelet therapy with aspirin and a thienopyridine (6365) have achieved the currently accepted 30-day ST rate of 1%. Reports of late DES thrombosis, often in association with cessation of antiplatelet therapy (9,13,19,37,38,59), suggest that long-term combined antiplatelet therapy might be appropriate. A recent science advisory has recommended lengthening the duration of dual antiplatelet therapy to 1 year after PCI and that elective surgery should be postponed for 1 year (66). The efficacy of increasing the maintenance dose of clopidogrel to 150 mg daily in patients with suspected clopidogrel resistance is unknown (67).

Percutaneous coronary intervention for emergent ST is often suboptimal, and ST recurs in 12% of these patients

Drug-Eluting Stent Thrombosis 2003-2004: Occasional case reports of late stent thrombosis after DES began to emerge First big bang: March 2006 ACC Atlanta Presentation of the BASKET-LATE Investigators 988 CONSECUTIVE (non-selected) patients randomized 2:1 DES:BMS 746 patients alive without MACE 6 months after coronary stenting; CLOPIDOGREL stopped:BMS Vision stent, Guidant Corp: 281 SES: 264 PES: 281 Clopidogrel stopped at 6 months and then followed for another 12 months

Current status of DES

The data on the two previously approved DES have demonstrated a significant reduction in the need for repeat revascularization vs BMS Recently the rare but catastrophic event of late stent thrombosis was shown to be increased with these DES compared to BMS However, any increased incidence of LST

Timing of stent thrombosis with BMS

(A) 10 8 6 n 4 2 0 (B) (B) 0 100 100 80 80 60 60 40 40 20 20 0 0 30 60 Days after PCI 120 600

Acute and subacute stent thrombosis ( 30 days) are in yellow, late stent thrombosis (> 30 days) in yellow. (B) Cumulative incidence of stent thrombosis following bare-metal stent implantation. Wenaweser P et al. EHJ. 2005;26:1180-1187.

30 60 90 120 600 30 60 90 120 600 Days after PCI (A) incidence of stent thrombosis (n = number of stent Days after PCI day) following bare-metal stent implantation. thromboses per 0

Percent of patients Percent of patients

BASKET-LATE: Late Catch up Overall (0-18 month) rates of death and MI were the same: BMS 7.5% vs DES 8.4% p=0.63 First 6 months Death and MI: BMS 12.1% vs DES 7.2% p=0.02 AFTER DISCONTINUATION of CLOPIDOGREL (months 7-18) Death: BMS 0% vs DES 1.2% MI: BMS 1.3% vs DES 4.1% Death and MI: BMS 1.3% vs DES 4.9% (p=0.03) All 6 deaths in the DES group 20/23 MI in the DES group Hypothesis generating, to say the least Pfisterer et al J Am Coll Cardiol 2006;48:2584-91

Meta analyses presented: ESC European Society of Cardiology meeting Barcelona September 2006 Death/Q wave MI 2.6% TAXUS vs 2.3% BMS (p=0.66) Death/Q wave MI 6.3% Cypher vs 3.9% BMS (p=0.03) Camenzind and Nordmann et al Industry data: Cordis/Johnson and Johnson and Boston Scientific FDA: Initial Statement on Coronary Drug Eluting Stents, September 14th 2006 FDA: Special Expert Advisory Committee, December 7th and 8th 2006 New England Journal of Medicine: March 8th 2007

With the introduction of P2Y-receptor antagonists (ie, ticlopidine, clopidogrel) for platelet inhibition in combination with acetylsalicylic acid, the incidence of stent thrombosis decreased substantially in stable patients to levels as low as 1%.5 Most of the events occurred within the first 10 days after implantation; indeed, stent thrombosis after the first month was extremely rare with BMS.6,7

Numerous reports describe the occurrence of acute (24 hours), subacute (30 days), late (30 days), and very late (12 months) stent thrombosis after DES implantation.8,13,16 true incidence of stent thrombosis may be underestimated in clinical trials and could occur at substantially higher rates in the real-world setting, where morecomplex lesions are treated

The most important risk factors for acute and subacute stent thrombosis are primary stenting in ST-segment elevation myocardial infarction and acute coronary syndromes.20,26 Additional risk factors include stent length, congestive heart failure, and a prothrombogenic state, such as metastatic cancer.19,20,26,27 One of the most significant risk factors for late and very late stent thrombosis appears to be discontinuation of antiplatelet therapy.26,27 Other predictors are stent underexpansion and residual reference segment stenosis

Outcome after Drug-eluting stent versus Bare-metal stent implantation: A network meta-analysis of 38 trials with 18,023 pts No difference in death or myocardial infarction up to 4 years follow-up

Stettler et al, Lancet 2007:370:937

Antiplatelet Therapy Post PCI Stents are foreign bodies in the vessel wall and thus induce platelet adhesion and balloon inflation causes Vascular injury leading to activation of the coagulation cascade. with exposure of thrombogenic molecules of the subintima and media (including plaque material) to the blood stream. As a consequence, only potent platelet inhibition made the procedure feasible, and antiplatelet hyporesponsiveness has been associated with an increased risk for stent thrombosis.31 In line with this observation, discontinuation of antiplatelet therapy has been observed to be particularly associated with DES thrombosis. 8,16,32 The appropriate duration of the long-term antiplatelet regimen for prevention of DES thrombosis remains to be assessed in randomized prospective trials; at present, a course of 12 months of dual-antiplatelet therapy may be considered especially in high-risk, real-world patients.

The data on the two previously approved DES have demonstrated a significant reduction in the need for repeat revascularization vs BMS Recently the rare but catastrophic event of late stent thrombosis was shown to be increased with these DES compared to BMS However, any increased incidence of LST appears to be offset by a reduction in downstream revascularization events prevented by DES

Stent thrombosis:
Procedure, product, patient
Procedure Stent apposition dissection

Product Polymer drug

Stent thrombosis

Patient Higher risk AP compliance

Late stent thrombosis DES: Factors to consider

Discontinuation of antiplatelet therapy

Delayed endothelialization

Late stent Late stent thrombosis thrombosis

Late incomplete apposition

Polymer hypersensitivity/ inflammation

Stent thrombosis rates

According to select patient characteristics
29.0%

8.7% 5.5% 3.5%

Bifurcations

3.2%
ULM

2.6%
Diabetes

1.3%
UA

*Antiplatelet therapy discontinuation

Prior brachy

Renal failure

*Premature discontinuation. *Iakovou et al. JAMA. 2005;293:2126-2130.

Premature discontinuation of antiplatelet therapy is the most important predictor of stent thrombosis after implantation* Results: At 9 month follow-up, 29 patients had stent thrombosis (1.3%) Among the 29 patients, 13 died (case fatality rate 45%)

Common reasons for discontinuation include: 41% Surgical procedures 35% Intolerance to bleeding 24% Noncompliance

Delayed endothelialization Cypher vs BMS

Sirolimus-eluting stent 100 75 50 25 0 Percent

Conclusions:

Incomplete coverage

Complete coverage

Grade 0 0 25 50 75 100 Percent

Grade 1

Grade 2

Grade 3

86.7% of Cypher stents had incomplete coverage (Grades 0-1)

0% of BMS had Bare-metal stent incomplete Grade 0 was defined as stent struts that were fully visible, similar to immediately after implantation. coverage Grade 1 was defined as stent struts that bulged into the lumen and, although covered, were still transparently visible. Grade 2 was defined as stent struts that were visible, but not clearly seen (ie, they were translucent). Grade 3 was defined as stent struts that were not visible by angioscopy (ie, they were embedded in the neointima). (Grades 0-1) Kotani et al. JACC. 2006;47:2108-2111.

Causes of Aspirin Resistance

Reduced bioavailability of aspirin Poor compliance Inadequate dose Reduced absorption or increased metabolism Altered binding to COX-1 Concurrent intake of certain NSAID (ibuprofen, indomethacin) Other sources of TX production Not blocked by aspirin (ex. COX-2 in monocytes, macrophages, EC) Alternative pathways of PLT activation Not blocked by aspirin (ex. RBC) Increased PLT sensitivity to collagen & ADP

Increased turnover of PLT By BM in response to stress (ex. CABG) Newly formed PLT unexposed to aspirin during the 24hr dose interval (aspirin half life 20min) Genetic polymorphism COX-1, COX-2, TXA2 synthase etc. PLT Rc (Ia/IIa, Ib/V/IX, IIb/IIIa, collagen,vWF) Factor XIII Loss of the antiplatelet effect of aspirin with prolonged administration (Tachyphylaxis ) Non-atherothrombotic causes of vascular events

Clopidogrel : mechanism

Causes of Clopidogrel Resistance Absorption Metabolism, Drug interaction CYP3A4 activity (Lau WC, et al. Circulation 2004) CYP3A5 polymorphism (Suh JW, et al. CMAJ 2006) CYP2C19 polymorphism (Hulot JS, et al. Blood 2006) P2Y12 Rc polymorphism Controversial Pro ; Cerebrovascular ds (Ziegler S, Stroke 2005), PAD (Fontana P, Circulation 2003) Cons ; CAD (Smith SM, Platelets 2006/ Angiolillo DJ, Thromb Res 2005)

LTA (light transmittance aggregometry ) Platelet aggregation Maximal percent change in light transmittance from baseline Platelet rich plasma Chrono-log 400 series, 500 series Pre-treatment Clopidogrel post 1wk *Blue responder aggregation: 27% *Black- nonresponder aggregation: -1%

Definition of resistance
Aspirin resistance 0.5mg/mL AA-induced platelet aggregation 20% and 5M/L ADP-induced platelet aggregation 70% Clopidogrel resistance Absolute difference between baseline and post-treatment aggregation (aggregation) 10% in response to both 5 & 20 M/L ADP

VerifyNowTM (Ultegra) RPFA

VerifyNowTM Aspirin Assay VerifyNowTM IIb/ IIIa Assay VerifyNowTM Clopidogrel Assay

Definition of resistance
Aspirin Aspirin reaction unit (ARU) 550 inadequate platelet inhibition by Aspirin

Duration of Dual Antiplatelet Therapy Acute stent thrombosis is a dreaded complication of PCI. It is rare but is typically associated with catastrophic consequences including myocardial infarction and sudden death. Incidence is in general <1% with dual antiplatelet therapy and high-pressure stent deployment. The majority of cases happen early poststenting . Dual antiplatelet therapy with aspirin plus clopidogrel is therefore mandatory initially in patients who had coronary stents implanted.

1. 2. 3. 4.

Patients already taking daily long-term aspirin therapy should take 75 mg to 325 mg of aspirin before PCI is performed. (Level of Evidence: A) 2. Patients not already taking daily long-term aspirin therapy should be given 300 mg to 325 mg of aspirin at least 2 hours and preferably 24 hours before PCI is performed. (Level of Evidence: C) 5. 3. After PCI, in patients without allergy or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least 1 month after BMS implantation, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxeleluting stent implantation, after which daily long-term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg. (Level of Evidence: B)

A loading dose of clopidogrel,* generally 600 mg, should be administered before or when PCI is performed. (Level of Evidence: C) In patients undergoing PCI within 12 to 24 hours of receiving fibrinolytic therapy, a clopidogrel oral loading dose of 300 mg may be considered. (Level of Evidence: C) For all post-PCI stented patients receiving a DES, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. For post-PCI patients receiving a BMS, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks).

1. Continuation of clopidogrel therapy beyond 1 year may be considered 2. in 3. patients undergoing DES placement. (Level of Evidence: C)

ptimal duration of dual antiplatelet therapy is ontroversial, ut a minimum period of 4 weeks for BMSs is widely ccepted.

Table 1 Relative contraindication to DESs that would favor use of BMSs 1. Adherence to prolonged DAPT? Polysubstance abuse Dementia Limited financial means 2. Bleeding risk? a. Known bleeding disorder Gastric ulcer Esophageal varices Diverticulosis b. Potential bleeding disorder (lifelong warfarin) Mechanical heart valve Atrial fibrillation Prothrombotic disorder 3. Surgery within the next year? Many procedures require termination of antiplatelet

following UGIH and/or endoscopic treatment of PUD to allow for full mucosal healing. Several studies have shown a therapeutic benefit of PPIs in patients using NSAIDs chronically and/or patients with confirmed H. pylori infection[34,35]. After initial mucosal healing has been achieved, is there a benefit to long-term PPI use for secondary prophylaxis? Studies have shown that in patients who have PUD complicated by bleeding, there is a 33% risk of rebleeding in 1-2 years. Furthermore, there is a 40%-50% rebleeding risk over the subsequent 10 years following the initial episode of bleeding[13]. Randomized prospective trials have demonstrated a benefit to long-term acid-suppression therapy in two settings: chronic NSAID users and H. pylori-infected patients. As demonstrated in a 2001 New England Journal of Medicine article by Chan et al[34], in patients taking NSAIDs other than acetylsalicylic acid (ASA) who were concomitantly infected with H. pylori, omeprazole provided added protection