#128 Aspirin Overhyped and Overused

December 3, 2018 | By Justin Berk

Aspirin’ to figure out if ASA can help prevent a heart attack? Interpreting all the new trials doesn’t have to cause chest pain! Join Dr. Ambarish Pandey from UT Southwestern as he helps The Curbsiders ASCEND the mountains of the latest studies to ARRIVE at some well-informed conclusions on the role of aspirin in primary prevention for cardiac events. The team also discusses secondary prevention, aspirin and dual (or triple) antiplatelet therapy, and whether it’s okay to stop giving aspirin to older adults without known CAD (Spoiler alert: it’s okay). ACP members can visit https://acponline.org/curbsiders to claim free CME-MOC credit for this episode and show notes (goes live 0900 EST).

Full show notes available at http://thecurbsiders.com/podcast. Join our mailing list and receive a PDF copy of our show notes every Monday. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com.

Credits

Written and produced by: Justin Berk MD, Matthew Watto MD

CME questions by: Justin Berk MD

Hosts: Matthew Watto MD, Paul Williams MD, Stuart Brigham MD

Edited by: Matthew Watto MD and Chris Chiu MD

Guest: Dr. Ambarish Pandey MD

Aspirin Pearls

1. The bleeding risk from aspirin (ASA) is likely worse than benefit of ASA in primary prevention of major adverse cardiac events “MACE” – (ARRIVE, ASCEND, ASPREE trials).
2. Aggressive reduction of other cardiac risk factors (eg BP control, smoking cessation) is more beneficial than aspirin therapy for primary prevention of MACE. (Ridker NEJM 2018)
3. Statin therapy has a much greater role than aspirin to prevent adverse cardiac events (Ridker NEJM 2018).
4. For elderly patients on long term aspirin for primary prevention, it is safe (and encouraged) to discontinue aspirin therapy. (ASPREE NEJM 2018)
5. Risk for recurrent cardiac events decreases as more times passes from an acute cardiac event (eg STEMI with stent placement). Keep this in mind when balancing bleeding risk with the long term use of antiplatelet agents and anticoagulants. -Dr Pandey’s expert opinion
6. NHANES data suggest a high percentage of patients are taking aspirin for primary prevention. This might make a nice article in SHM’s “Things we do for no reason” #twdfnr series. -Dr Watto’s non-expert opinion.

Aspirin – In-depth Show Notes

Definitions

MACE: Major adverse cardiac event is usually defined as myocardial infarction (MI), stroke, or vascular death. Note #1: Detection of clinically insignificant, non-fatal MI is probably more common with higher sensitivity troponin testing. Note #2: MACE has different and stricter (less inclusive) definition than “clinical ASCVD” used in the 2018 AHA/ACC lipid guideline (see next).

Clinical ASCVD: The recently published 2018 AHA/ACC lipid guidelines define clinical atherosclerotic cardiovascular disease (ASCVD) as “acute coronary syndrome (ACS), those with history of myocardial infarction (MI), stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin.” (Grundy et al. JACC 2018)

ASCVD Risk: Risk calculators like Framingham, the Pooled Cohort equations, or MESA typically, provide a 10 year risk estimate for ASCVD defined as “heart attack, stroke, stable angina, coronary revascularization, and peripheral arterial disease” –Ray et al. Eur Heart J 2014 .

Primary prevention: Prevention of cardiac events and mortality in patients WITHOUT a history of previous MACE – Mainous et al J Am Heart Assoc 2014.

Secondary prevention: Prevention of recurrent cardiac events or mortality in patients WITH a previous history of MACE* – Mainous et al J Am Heart Assoc 2014.

*Note: Some sources define secondary prevention differently and consider patients with coronary or peripheral artery disease, and atrial fibrillation to be at high risk –Antithrombotic Trialists’ Collaboration – BMJ 2002 PMID: 11786451. We stick to the more simple definition of “Any patient with prior heart attack, or stroke”.

DAPT: Dual antiplatelet therapy = aspirin + another antiplatelet. Typically, clopidogrel, ticagrelor, prasugrel, etc.

Bleeding: Usually defined as intracranial bleeding, sight-threatening bleed of the eye, GI bleed or bleeding event resulting in hospitalization, transfusion, or fatality.

Number needed to treat (NNT): The number of patients that must receive the treatment in order to observe the benefit.

Number needed to harm (NNH): The number of patients that must receive the treatment in order to observe the harm.

ASA: Aspirin

DOAC / NOAC: Direct (Novel) Oral Anticoagulation (e.g. rivaroxaban)

Aspirin for Primary prevention

First question

Does this patient have a history of MI or stroke?

• This is a key decision point between primary or secondary prevention.
• A patient with calcified coronary arteries seen on a CT chest is still categorized as primary prevention.
• The term secondary prevention is used AFTER a cardiac event (see def. of MACE above) or revascularization e.g. percutaneous intervention (PCI), or coronary artery bypass graft (CABG).

Earlier trials

Two large trials from the 1990s showed a beneficial effect for ASA in patients without prior MACE. Specifically, they found a decrease in MI (Physicians Health Study 2005) or stroke (Women’s Health Study 1989), but NOT mortality.

• The event rates in these studies was much higher than that observed in the newer trials discussed below.
• NEJM Editorial: Control of cardiac risk factors was different back then e.g. there was increased smoking in the original cohorts. Naturally, as risk factors decrease the absolute risk reduction from aspirin decreases. Consequently, the number-needed-to-treat to see a beneficial effect also increases.

Current recommendations

Based on Physicians’ and Women’s Health studies and other similar studies: the USPSTF recommends using ASA for primary prevention in patients with a 10 year Framingham risk score of 10% or higher at age 50 – 60 years. Dr. Pandey notes that ASA’s bleeding risk is often in excess of its benefit. Thus, he recommends starting a statin before ASA because of better evidence, less bleeding risk, and fewer side effects.

• (In fact, “nocebo effect” can partially explain statin-induced myalgia.)
• [Check out ACC statin intolerance calculator]

Discussion of New Trials

ARRIVE Trial

STUDY POPULATION: Moderate risk (ASCVD > 20%) adults without diabetes.

SAMPLE SIZE: RCT with 12,000 patients and 5 year follow-up.

RATE OF MACE: ~5% (lower than traditional studies)

RESULTS: ASA showed no reduction in MACE or mortality. There was a 2-fold higher risk of bleeding in ASA vs placebo.

ASCEND Trial

STUDY POPULATION: Adults with diabetes
NEJM Quick Take Video

SAMPLE SIZE: RCT with 15,000 patients and 7.5 years follow-up

RATE OF MACE: 8-9% (higher than ARRIVE trial demonstrating high ASCVD risk in diabetes).

RESULTS: ASA showed 12% reduction in MACE with 29% higher risk of significant bleeding.

Stuart’s back of the envelope calculations:

• Absolute Risk Reduction was 1.1% with ASA vs placebo
• NNT: Prescribe aspirin to 673 patients per year to prevent one MACE.
  NNH: Prescribe aspirin to 823 patients per year to cause one bleeding event.

ASPREE Trial

STUDY POPULATION: Age > 70 years old.

SAMPLE SIZE: RCT with 20,000 patients and 5 years follow-up

RATE OF MACE: 10%

RESULTS (3 papers):

• All-cause mortality was 14% higher with patients on aspirin (related to cancer).
• ASA did not increase disability-free survival. The rate of bleeding was 38% higher in the ASA group.
• ASA did not decrease the rate of MACE.

Stable Coronary Artery Disease

• Note: ASA use in a patient with known, but asymptomatic CAD seen on imaging (no history of MACE), is STILL considered primary prevention.
• Additionally, ASA use in a patient with chronic stable angina and no history of MACE is STILL consider primary prevention.
• A coronary artery calcium (CAC) score, can be used to calculate ASCVD risk with the MESA calculator (BUT n.b. this calculator is designed for for statin eligibility, NOT to decide who needs aspirin).
• Dr. Pandey’s expert opinion: Aggressive risk factor modification is better than aspirin for primary prevention e.g. Exercise, diet, new diabetes medications (SGLT2 inhibitors or GLP-1 agonists), and statin treatment would all be better than aspirin.

Aspirin for Secondary prevention

• Lifelong low dose aspirin (usually 81 mg daily in the US) is recommended for secondary prevention, unless there is a contraindication (e.g. significant bleed). (Antithrombotic Trialists’ Collaboration – BMJ 2002 PMID: 11786451).
• If a patient has had coronary or peripheral revascularization (stent or arterial bypass), MI or stroke, then ASA use is considered secondary prevention. 

Note: Some sources like 2018 AHA/ACC Lipid Guideline, 2002 Anti-thrombotic Trialists Collaboration use a broader definition of secondary prevention e.g. include stable angina and peripheral artery disease.

Case 1 – PCI for stable CAD

If a patient without prior MACE undergoes percutaneous intervention (PCI) with stenting for stable coronary artery disease (CAD), then continue DAPT for 6 months. Consider stopping clopidogrel (or other P2Y12 inhibitors) after this initial 6 months. Aspirin should be continued lifelong as monotherapy. -Dr Pandey’s expert opinion

Case 2 – PCI for Acute coronary syndrome (e.g. acute STEMI)

Continue DAPT (i.e. ASA plus clopidogrel) for one year. Then, calculate a DAPT score (from DAPT study). If the DAPT score is 2 or higher and no bleeding stigmata, then continue DAPT for 30 months before stepping down to aspirin monotherapy -Dr Pandey’s expert recommendation.

Note: You need the stent diameter to calculate a DAPT score.

Antiplatelet and anticoagulant coprescription

Anticoagulants

These include the DOACs, warfarin, low molecular weight heparin, fondaparinux, etc. We will use DOACs to highlight case examples below, but the rules would be the same for other anticoagulants coprescribed with aspirin.

Case 1 – Patient on ASA for secondary prevention without prior PCI/stent, but now needs long-term anticoagulation (e.g. DOAC)

In a patient on aspirin once daily after a remote MACE without PCI/stent who then develops atrial fibrillation, Dr Pandey recommends dropping ASA while that patient is taking a DOAC (or warfarin). This is because antiplatelet plus anticoagulant increases bleeding risk (see Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy. UpToDate 2018).

Note: This group is not well studied and the above recommendation is expert opinion.

Shout out: Sparctool.com: Allows input of the CHA2DS2-VASc and HAS-BLED scores to visually compares medications, calculated benefit and bleeding risk. It’s awesome!

Case 2 – Patient on DAPT after PCI/stent, but now needs long-term anticoagulation (e.g. DOAC)

Dr Pandey recommends: Stop aspirin. Continue DOAC plus clopidogrel for 6-30 months based on patient’s indications for stenting and DAPT score (see ASA for secondary prevention above). Dr Pandey stops clopidogrel after the initial 6-30 months and continues DOAC as monotherapy to balance benefits with risk of bleeding.

Note: UpToDate article by Sarafoff et al states ”The optimal long-term antithrombotic regimen for patients who have successfully completed a period of 6 to 12 months of oral anticoagulant and a P2Y12 receptor blocker (P2Yi) has not been well studied. Most of our experts continue DOAC plus aspirin. For individuals at high ischemic risk, some experts continue with DOAC plus a P2Yi, usually clopidogrel.” (Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy. UpToDate 2018).

Dual versus Triple Therapy

Pioneer-AF PCI by Gibson CM et al NEJM 2016

In >2,000 patients with atrial fibrillation who underwent PCI/stenting, rivaroxaban 15 mg plus clopidogrel or rivaroxaban 2.5 mg twice daily plus DAPT had lower bleeding rates compared to “triple therapy” (warfarin plus DAPT) at 12 months without an increased rate of MACE.

RE-DUAL PCI by Cannon CP et al NEJM 2017

In >2000 patients with atrial fibrillation who underwent PCI, the risk of bleeding was lower among those who received “dual therapy” with dabigatran and a P2Y inhibitor than among those who received “triple therapy” with warfarin plus DAPT. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.

WOEST Trial by Dewilde CJM et al Lancet 2013

Dual therapy had significantly lower bleeding risk than triple therapy in patients with atrial fibrillation who underwent PCI/stenting without an increased risk of thrombotic events.

Dr. Pandey notes: “As you move away from event…prioritize bleeding over anticoagulation”

Time Stamps

• 00:00 Disclaimer, intro and guest bio
• 04:15 Guest one liner, book recommendation, career and research advice
• 11:07 Case of aspirin for primary prevention, aspirin’s public persona, and nocebo effects of statins
• 21:40 ARRIVE and ASCEND trials
• 28:14 Aspree trial
• 32:38 Coronary artery calcium; aspirin use for secondary prevention
• 37:42 Dual antiplatelet therapy and the DAPT score
• 41:25 Should we continue aspirin when a patient also needs a DOAC?
• 46:14 Should we continue DAPT in a patient who needs a DOAC (or warfarin)?
• 49:40 Deprescribing aspirin for primary prevention in older adults?
• 50:51 Closing remarks
• 52:33 Outro

Goals and Learning Objectives

Goal

Listeners will identify common uses of aspirin for cardiovascular risk reduction and evaluate the risk and benefits of aspirin use in common clinical scenarios

Learning objectives

After listening to this episode listeners will…

1. Define primary and secondary prevention
2. Evaluate and distinguish between the risks and benefits of aspirin use for primary and secondary prevention
3. Review recent studies evaluating the use of aspirin for primary prevention
4. Individualize the decision for aspirin use including dose and duration of therapy
5. Deprescribe aspirin in patients unlikely to receive benefit
6. Determine when to stop aspirin therapy in a patient who requires new anticoagulation

Disclosures

Dr Pandey reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures.

Links from the show

1. Tupac Live at Coachella (EXPLICIT) https://youtu.be/uJE8pfPfVRo
2. Calvin and Hobbes collection
3. Physicians Health Study
4. Women’s Health Study
5. NEJM editorial by Ridker PM. Should Aspirin Be Used for Primary Prevention in the Post-Statin Era?  NEJM 2018; (Subscription required)
6. USPSTF On Use of ASA for Prevention of CVD and Cancer published April 2016.
7. Nocebo effect can explain statin-induced myalgia. (Pedro-Botet & Rubies-Prat, 2017)
8. Sparctool.com for Afib to compare/individualize stroke and bleeding risk
9. ARRIVE Trial by Gaziano JM et al. Lancet Aug 2018.
10. ASCEND Trial by The ASCEND Study Collaborative Group NEJM Sep 2018. Check out the NEJM Quick Take Video summarizing ASCEND.
11. ASPREE Trial looking at mortality, disability-free survival, & rate of MACE. by McNeil JJ et al. NEJM Sep 2018.
12. DAPT score calculator from acc.org
13. Japanese study of ASA for Primary Prevention by Ikeda et al JAMA 2014

Permalink URL

http://thecurbsiders.libsyn.com/128-aspirin-overhyped-and-overused ; https://bit.ly/2Kykgpl

Citation for guest CV

Pandey, Ambarish. Guest expert. “#128 Aspirin: Overhyped and Overused”. The Curbsiders Internal Medicine Podcast http://thecurbsiders.com. December 3, 2018. http://thecurbsiders.libsyn.com/128-aspirin-overhyped-and-overused