ASA PLAVIX AND PREOPERATIVE OPTIMIZATION

John Hann, MD

QUESTIONS: WHICH ANTI-PLATELETS DO YOU STOP AND WHEN?

1. 65 yo M with history of stroke on ASA PreOp eval for cataracts surgery

2. 65 yo M with RCRI of 4 on ASA undergoing open cholecystectomy for malignant neoplasm resection

3. 65 yo M with DES in 2007 on ASA and Plavix undergoing laparoscopic cholecystectomy for

cholelithiasis

4. 65 yo M with DES on Halloween of 2017 (4 weeks ago) on ASA and Plavix undergoing TURP for BPH

5. 65 yo M with DES in 2012 on ASA and Plavix undergoing malignant, infratentorial neoplasm resection

6. 65 yo M with DES on Thanksgiving of 2017 on ASA and Plavix undergoing cystectomy for urothelial

cancer

POISE-2: PERIOPERATIVE ISCHEMIC EVALUATION 2 2014

international, randomized, controlled trial designed to separately evaluate the effects of aspirin versus placebo and clonidine versus placebo in patients undergoing noncardiac surgery.

Clonidine was used vs ASA because of the belief that clonidine may suppress the sympathetic nervous system thus possibly preventing MI… it did not.

Results showed that Clonididine worsened outcomes

Patients also received aspirin or placebo just before surgery and continued receiving it daily throughout the postoperative period.

Patients in both ASA strata receive the same trial ASA intervention (ie, either ASA 100 mg or matching placebo). For the first dose prior to surgery (goal 2-4 hours), they take 2 tablets orally. Starting on the day after surgery, patients take 1 tablet daily for 30 days in the Starting Stratum and 7 days in the Continuation Stratum, after which they resume their regular ASA.

ELIGIBILITY CRITERIA FOR POISE 2

EXCLUSION CRITERIA FOR POISE 2

Side note: The initiation strata of ASA had lower risk of stroke compared to placebo (3 strokes in ASA vs 12 in placebo). However, in the continuation strata there were more strokes in the ASA group (13 in ASA and 7 in placebo). Combined the data do not show statistically significant differences of combined ASA takers.

CONCLUSION OF THIS STUDY

Even for individuals with significantly elevated RCRI, there was no difference in outcomes of those on aspirin and those not on aspirin EXCEPT that those who were not on ASA had an increased risk for major bleeding and dialysis

But: There was one important subgroup of participants who were not singled out in the results.

WHAT HAPPENS WHEN ASA IS STOPPED IN THE SETTING OF STENT

Biondi-Zoccai et al. performed a meta-analyses of 50,279 patients for secondary prevention for coronary artery disease which showed that the cardiac complication rate was three times higher after ASA withdrawal and increased even more in patients with coronary stents.

There was, on average, a 10.6-day period between withdrawal from ASA and thrombotic events (8.5 days for coronary symptoms).

“A survey conducted on 374 interventional cardiologists found that although there is agreement among interventional cardiologists on the optimum delay for surgery after stenting, on the need for BMS or balloon angioplasty alone if early noncardiac surgery is needed, and on treatment of perioperative thrombosis, there is significant inconsistency on the optimum antiplatelet therapy for patients who need surgery early after stent implantation”

The Poise-2 trial conclusion did not explicitly address this population

THANK YOU AMISH: LOW-DOSE ASPIRIN TO REDUCE THE RISK FOR MYOCARDIAL

INFARCTION AMONG PATIENTS WITH CORONARY STENTS UNDERGOING NONCARDIAC SURGERY

Approximately 5% to 25% of patients having PCI may require noncardiac surgery within 5 years after stent implantation

Cardiovascular adverse events are the leading cause of morbidity and mortality after noncardiac surgery, and myocardial infarction accounts for most of these adverse events

EFFECT OF ASPIRIN ON RISK FOR COMPOSITE OF DEATH AND NONFATAL MYOCARDIAL INFARCTION AMONG PATIENTS WITH A HISTORY OF PERCUTANEOUS CORONARY INTERVENTION.

Uncertainty

Uncertainty

EFFECT OF ASPIRIN ON RISK FOR MAJOR BLEEDING AMONG PATIENTS WITH A HISTORY OF PERCUTANEOUS CORONARY INTERVENTION.

The results, then, suggest that for every 1000 patients with prior PCI who have noncardiac surgery, administration of perioperative aspirin would prevent 59 myocardial infarctions (CI, 10 to 108 myocardial infarctions) and cause 8 major bleeding

On the basis of this study's findings, 17 patients with prior PCI (95% CI, 9 to 100 patients) would need to be treated with aspirin to prevent 1 myocardial infarction during the perioperative period,” the editorialists wrote. “If we consider the 22% higher relative risk for major or life-threatening bleeding events associated with aspirin, only surgical procedures with a very high baseline bleeding risk (≥26%) would neutralize aspirin's ischemic benefit.”

The study included only 470 patients with prior PCI and they had few events, which creates imprecision in the estimates of effect.

TAKE HOME FROM THIS SUB GROUP ANALYSIS

Patients with prior PCI do have significantly higher risk of MI if ASA is held

It is unclear if this population has a higher bleeding risk.

Regardless, the bleeding risk of the surgery must be much higher to outweigh the risk of MI

HOW LONG TO HOLD ASA

If you need to hold ASA, how long should you hold it? Common recommendation are to hold the drug 7–10 days before surgery to ensure that the platelets are functioning once again well.

However, mean time for occlusion of stent is approximately 10 days following discontinuation of ASA, so what is optimal time?

The following study consisted of 14 healthy, untreated, male volunteers aged 20–60 years and 58 male and female (all postmenopausal) patients receiving regular treatment with 100 mg aspirin who were scheduled for elective orthopaedic or urological surgery at a major tertiary medical centre.

CONCLUSIONS

“The recommendation to wait 7–10 days until platelet function recovers is based on the assumption that aspirin inhibition of platelet COX is irreversible and neutralizes platelets for their whole lifespan. However, in the present study, according to the aggregometry measurements with both agonists, platelet function recovered earlier: after 3 days in volunteers and after 4 days in most patients.”

To explain this finding, we suggest that the effect of aspirin on megakaryocytes in bone marrow is not permanent, in contrast to platelets that are permanently impaired by the action of aspirin and are later removed from the circulation.

Weaknesses of the study: More men then women

They chose not to apply the same protocols of the two groups since it would be “unethical” to do daily blood draws of the patients

They did not evaluate the clinical response

They had a small sample size.

CONCLUSIONS CONTINUED

In the majority of the patients treated with aspirin, platelet function recovers in 4 days after aspirin cessation compared with 3 days in healthy volunteers.

Despite the fact that platelet function recovers after 4 days in the majority of patients, some patients might nevertheless have delayed recovery. We, therefore, suggest that the duration of aspirin cessation before elective surgical procedures with a high risk of potential bleeding should be 6 days, and that platelets should be monitored by aggregometry if this is not feasible.

From the POISE 2: Studies have suggested that hemostasis is unimpaired if at least 20% of the platelets have normal COX-1 activity and 12% of circulating platelets are replaced every 24 hours. Therefore, stopping aspirin 72 or more hours before surgery may be adequate to minimize the risk of perioperative bleeding.

PERIOPERATIVE ANTIPLATELET IN THE SETTING OF DES

PCI-CURE study (2002) in in which 2658 patients with ACS underwent PCI. Clopidogrel w/ ASA vs ASA alone. 31% reduction (p = 0.002) of cardiovascular mortality or myocardial infarction (MI) rate was observed in the clopidogrel group

The difference between both groups appears during the first 3 months, and stays constant or slightly increases up to 12 months.

Updated guidelines in 2016: In patients with ACS (NSTE-ACS or STEMI) treated with coronary stent implantation who have tolerated DAPT without a bleeding complication and who are not at high bleeding risk (e.g., prior bleeding on DAPT, coagulopathy, oral anticoagulant use), continuation of DAPT (clopidogrel, prasugrel, or ticagrelor) for longer than 12 months may be reasonable (Class IIb).

RECOVERY OF PLATELET FUNCTION AFTER DISCONTINUATION OF CLOPIDOGREL TREATMENT IN HEALTHY VOLUNTEERS

Flow Cytometry

Adenosine diphosphate (ADP, 30

µM)-induced platelet responses

were almost completely inhibited

by clopidogrel.

Thus, our data are

compatible with the view

that the inhibitory effects of

clopidogrel are terminated

by de novo formed platelets.

…after discontinuation of

clopidogrel treatment, platelet

function gradually recovers and

that a complete restoration of

ADP-induced platelet responses

occurs 7 days after the last

clopidogrel dose

CLINICAL RELEVANCE: CURE TRIAL CLOPIDOGREL IN

UNSTABLE ANGINA TO PREVENT RECURRENT EVENTS

In a subgroup analysis of 912 patients who had stopped clopidogrel less

than 5 days before CABG surgery in the CURE trial (Yusuf et al 2001) there was

increased risk of minor bleeding (5.1% clopidogrel vs 2.4% placebo, p<0.001) and a trend towards an increased risk of major bleeding (9.6% clopidogrel vs 6.3% placebo, p=0.06) among patients in the

clopidogrel group compared with placebo. In contrast, there was no excess of major bleeding after CABG surgery among patients who discontinued

clopidogrel at least 5 days prior to surgery (4.4% clopidogrel vs 5.3% placebo; p=0.53).

CURE TRIAL APPLIED TO CARDIAC CASES, HOWEVER….

Evidence to continue Plavix:

A study of 647 patients undergoing vascular surgery and receiving DAPT with clopidogrel and ASA up to the day of surgery concluded that maintenance of DAPT is not associated with increased bleeding complications or transfusion requirements

Another registry of 10 406 patients undergoing vascular procedures (carotid endarterectomy, lower extremity bypass, endovascular aneurysm repair, or open abdominal aortic aneurysm repair) found that bleeding, transfusion requirements, and reoperation rates for bleeding were similar among the four patient groups based on an antiplatelet regimen (ASA vs ASA plus clopidogrel vs clopidogrel vs no antiplatelet therapy).

Patients undergoing thoracic surgery do not seem to experience increased bleeding while on clopidogrel, but the incidence of perioperative MI is significantly higher among patients with stents discontinuing DAPT in the perioperative period

Urological surgery, with the exception of transurethral resection of prostate, can be safely performed while on DAPT.149–151 However, customary practice among urologists is to stop DAPT before cystoprostatectomy or nephrectomy due to concerns of increased bleeding.152

In patients undergoing intra-abdominal surgery, data suggest that these operations can be safely performed while continuing DAPT.153

Evidence to Hold Plavix:

Severe complications are eight times more likely after Mohs procedures in patients on DAPT than in control subjects taking ASA monotherapy

Patients on DAPT undergoing orthopaedic surgery (especially patients undergoing hip and knee replacement) have an increase in bleeding complications and increased risk of transfusion in the operating theatre or in the first 24 h after operation.145 Another study concluded that stopping clopidogrel 5 days before operation might decrease the risk of complications, although mortality is not influenced.146 These findings are in contrast with data from patients undergoing hip fracture surgeries, who demonstrate no increase in transfusion requirements when taking clopidogrel.

ACC/AHA RECOMMENDATIONS DIRECTLY FOLLOWING DES

Class I

1. Elective noncardiac surgery should be delayed 14 days after balloon angioplasty (Level of Evidence: C) and 30 days after BMS implantation (99–101). (Level of Evidence B)

Elective noncardiac surgery should optimally be delayed 365 days after drug-eluting stent (DES) implantation (102–105). (Level of Evidence: B)

Class II

1. In patients in whom noncardiac surgery is required, a consensus decision among treating clinicians as to the relative risks of surgery and discontinuation or continuation of antiplatelet therapy can be useful.

. Elective noncardiac surgery after DES implantation may be considered after 180 days if the risk of further delay is greater than the expected risks of ischemia and stent thrombosis

TAKE HOME POINTS

For elevated risk surgery, even for elevated RCRI, ASA does not improve risk of MI and increases risk of bleed

For CAD with Stent, ASA has been proven to be beneficial perioperatively and should be continued in all but the highest risk bleeding surgery

ASA usually is out of the system by 5 days, but effects may be resolved in as little as 3 days

Plavix should be continued following DES for 180 days minimum, 365 best.

Can consider, with discussion with surgeon, continuing Plavix even on higher risk bleeding surgery

QUESTIONS: WHICH ANTI-PLATELETS DO YOU STOP AND WHEN?

1. 65 yo M with history of stroke on ASA PreOp eval for cataracts surgery

2. 65 yo M with RCRI of 4 on ASA undergoing open cholecystectomy for malignant neoplasm resection

3. 65 yo M with DES in 2007 on ASA and Plavix undergoing laparoscopic cholecystectomy for

cholelithiasis

4. 65 yo M with DES on Halloween of 2017 (4 weeks ago) on ASA and Plavix undergoing TURP for BPH

5. 65 yo M with DES in 2012 on ASA and Plavix undergoing malignant, infratentorial neoplasm resection

6. 65 yo M with DES on Thanksgiving of 2017 on ASA and Plavix undergoing cystectomy for urothelial

cancer

1. Very low risk bleeding, high risk stroke: Continue ASA

2. Higher risk bleeding (neoplasm), though elevated RCRI, no increased risk of MI, therefore hold ASA

3. Low risk surgery bleeding, high risk thrombosis, continue DAPT

4. Wait 365 days, elevated, but not 20% bleeding, therefore cont ASA, likely hold Plavix 5 days

5. High bleeding risk, closed space. Hold ASA 3-5 days, Plavix 5 days. Consider agglutination test

6. Tough: too soon for surgery which can wait weeks, but 6-12 months. Best to wait min until 4-6 weeks post

stent, then likely consider continue both after discussion of bleeding risk with surgeon.

REFERRENCES

POISE trial references

ASA in patients undergoing noncardiac surgery (POISE-2): http://www.nejm.org/doi/full/10.1056/NEJMoa1401105#t=article

Rational for Poise2 study: http://www.ahjonline.com/article/S0002-8703(14)00077-5/fulltext

Duration of platelets: http://www.thrombosisresearch.com/article/0049-3848(80)90334-5/pdf and https://www.ncbi.nlm.nih.gov/pubmed/16517326 and https://www.ncbi.nlm.nih.gov/pubmed/3933848?dopt=Abstract and https://www.ncbi.nlm.nih.gov/pubmed/7123514?dopt=Abstract

REFERENCES

Antithrombotics in the setting of DES

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485386/

AHA guidelines: https://ac.els-cdn.com/S0735109714055375/1-s2.0-S0735109714055375-main.pdf?_tid=0829dad4-c7dc-11e7-8884-00000aacb361&acdnat=1510513530_b09e0e5b0e59aaff306bfdc4b6b6757d

Amish send out article

Editorial: https://acphospitalist.org/weekly/archives/2017/11/15/1.htm?utm_campaign=FY17-18_NEWS_HOSPITALIST_DOMESTIC_111517_EML&utm_medium=email&utm_source=Eloqua

Primary article: http://annals.org/aim/article-abstract/2663288/aspirin-patients-previous-percutaneous-coronary-intervention-undergoing-noncardiac-surgery

PLATELET FUNCTION TIME ASA

Platelet function recovery after cessation of aspirin: preliminary study of volunteers and surgical patients

Zisman, Eliyahu; Erport, Angelika; Kohanovsky, Eugene; Ballagulah, Marc; Cassel, Aliza; Quitt, Miriam; Pizov, Reuven