dapt vs triple therapy, jacc

Question:

77 YOM with PMH of HTN, HLD, CAD, Paroxysmal AF and DM2 was admitted and treated for STEMI with PCI X 3 stents in LAD, LCirc. currently in AF is now ready for discharge.

What Anticoagulation/Antiplatelet therapy would you discharge patient with?

Use and Outcomes of Triple Therapy Among Older Patients With Acute Myocardial Infarction and Atrial FibrillationJACC VOL. 66 NO. 6 2015 AUGUST 11 2015:616 – 2 7

Khushboo M. Gandhi, MD

PGY1 Internal Medicine St. Luke’s Hospital

09-02-2015

BACKGROUND

77 YOM with PMH of HTN, HLD, CAD, Paroxysmal AF and DM2 was admitted and treated for STEMI with PCI X 3 stents in LAD, LCirc. currently in AF is now ready for discharge.

Current guidelines for Anticoagulation-Antiplatelet Therapy ?

Current Guidelines

AF Anticoagulation for thromboembolic px - at average or higher risk for stroke but not at prohibitive risk for bleeding

Acute MI with PCI

Dual antiplatelet therapy (DAPT) - major adverse cardiac events (MACE) and stent thrombosis

Study Goal:

To determine appropriate antithrombotic therapy - Older patients + MI + AF + PCI

BACKGROUND

Previous Studies:❏ Treated with triple therapy relative to DAPT - lower risk of MACE but higher bleeding risk❏ Paucity of randomized data - shown variability in anticoagulant agent use acc. to stroke and bleeding risk❏ Most importantly - Older population underrepresented and understudied❏ Older patients at greater risk for

● AF-related stroke and MACE● Bleeding events

This Study:❏ Linked data from ACTION Registry–GWTG + Medicare Administrative claims❏ Opportunity to examine a large group of older MI patients with AF undergoing PCI❏ Main objectives:

● Describe the patterns of use of discharge triple therapy versus DAPT in older MI patients with AF treated by using PCI

● Characterize warfarin use patterns post-discharge● Compare the safety and effectiveness of triple therapy versus DAPT

ACTION Registry–GWTG

❏ National registry created in 2007 by the merger of the

National Cardiovascular Data Registry (NCDR) + ACTION Registry from the American College of Cardiology (ACC) + GWTG-Coronary Artery Disease (CAD) Program from the American Heart Association (AHA)

❏ Includes detailed clinical information on >5,00,000 patients with STEMI or NSTEMI in >800 participating US hospitals

❏ Objectives: to record information on:

Treatment patterns, Clinical outcomes, Drug safety and Overall quality of care (measured by adherence to ACC/AHA clinical guidelines) provided to patients with STEMI and NSTEMI.

❏ The registry has determined:

❏ The extent to which numerous factors such as age and gender can influence patient outcomes

❏ Ethnic differences in treatment patterns in patients presenting with STEMI

❏ The bleeding risk of patients presenting with MI who were treated with anticoagulant therapy

DATA SOURCES

Clinical and procedural data - ACTION Registry–GWTG (collected without unique patient identifiers)

Linked patients >= 65 years of age in the ACTION Registry–GWTG with Medicare claims data using indirect identifiers in combination (date of birth, sex, hospital identification, date of admission and date of discharge)

January 1 2007 through December 31 2010.

Longitudinal outcomes - Inpatient administrative data - Medicare Part A

Post-discharge warfarin and P2Y12 receptor inhibitor use - Medicare Part D data

Warfarin was the only anticoagulant agent available for clinical use

METHODS:

Identified 1,23,349 patients > 65 years of age at 683 sites ACTION Registry–GWTG + Medicare insuranceI

64.7% (79,750 patients from 502 sites) were linked to Centers for Medicare & Medicaid Services dataI

6,098 patients with❏ Acute MI ❏ Eligible for Medicare during the index discharge month ❏ History of AF or atrial flutter ❏ Underwent in-hospital PCI with stent placement (data collection form) at 1 of 405 hospitals

in the ACTION Registry–GWTG

❏ Excluded❏ Died during the index hospitalization (374) ❏ Transferred out to another acute care hospital (63)❏ Left against medical advice or discharged on comfort measures or to

hospice (74). ❏ Not discharged on both aspirin and a P2Y12 antagonist (clopidogrel

prasugrel or ticlopidine (444)

❏ Excluded (184)❏ Documented contraindication to warfarin (103)❏ Missing data on discharge warfarin use (16)❏ Non-index admissions for patients with multiple records (65)

AMI patients with AF or atrial flutter with stent placement discharged home on DAPT (5,143)

Final analysis population (4,959 patients; 400 sites)

OUTCOMES & DEFINITIONS:

❏ Primary effectiveness outcome:• MACE at 2 years

MACE = Death or readmission for MI or stroke (ischemic and hemorrhagic)

❏ Secondary effectiveness outcomes:• Individual components of the composite MACE outcome• Ischemic stroke alone

❏ Primary safety endpoint:• Bleeding readmission within 2 years after the index hospitalization

(Including ICH)

❏ Outcomes - Identified using ICD-9 codes from Medicare inpatient claims data.

❏ Patients were classified according to stroke risk and bleeding risk.• CHADS2 risk score• ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) risk score

ATRIA:

Anemia (Hb <13 g/dl in men <12 g/dl in women) ORSevere renal disease (GFR <30 ml/ min or dialysis dependent)

3

>75 years 2

Hypertension or Prior bleeding 1

>3 - High bleeding risk

CHADS2:

congestive heart failure Hypertension age >75 years or DM

1

History of stroke or transient ischemic attack. 2

For sensitivity of analysis:

❏ Post-discharge warfarin and P2Y12 inhibitor prescription fill information - Medicare Part D prescription claims database ❏ Examined Medication persistence at 90 days after discharge - defined as continuation of the medication prescribed at discharge

without a gap in filling >60 days ❏ Examined Warfarin initiation post-discharge - determining time to first warfarin prescription fill post-discharge.

❏ Variables used in propensity models:

❏ Age❏ Sex ❏ Body mass index ❏ Hypertension ❏ Dyslipidemia ❏ Diabetes ❏ Peripheral artery disease ❏ Prior MI ❏ Prior PCI ❏ Prior coronary artery bypass grafting (CABG) ❏ Prior heart failure ❏ Prior stroke ❏ Prior bleeding within 1 year ❏ Home medications (i.e. aspirin, beta-blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker statin) ❏ MI type (STEMI vs. NSTEMI) ❏ Signs and symptoms of heart failure at presentation or in-hospital ❏ Left ventricular ejection fraction (i.e. >40%, <40%, not evaluated) ❏ Baseline hemoglobin ❏ Baseline creatinine ❏ Arrival-to-cardiac catheterization time <48 h ❏ Multivessel disease ❏ Drug-eluting stent (DES) versus bare-metal stent use ❏ Discharge medications (i.e. angiotensin-converting enzyme inhibitor or angiotensin receptor blocker statin) ❏ Hospital region and teaching status❏ In-hospital major bleeding

❏ In-hospital major bleeding:

❏ Absolute hemoglobin decrease of >4 g/dl ❏ Intracranial hemorrhage ❏ Documented or suspected retroperitoneal bleed ❏ Any red blood cell transfusion with baseline hemoglobin >9 g/dl❏ Transfusion with baseline hemoglobin <9 g/dl with a suspected bleeding event. ❏ Only preoperative bleeding events in CABG patients were included❏ All variables had a missing rate <1%.

Assessed how the Discharge Therapy and Outcomes relationship differs in the following subgroups:a. Age >75 years Vs <75 years b. Female Vs male patientsc. High Vs low CHADS2 risk scored. High Vs low ATRIA bleeding risk scoree. DES Vs bare-metal stent usef. MI type (NSTEMI Vs STEMI).

Secondary analyses:

As a sensitivity study:

Landmark Analysis:● Examined the association between 90-day treatment status and subsequent MACE and bleeding outcomes.● Compared outcomes:

○ Discharged on warfarin + persistently on warfarin therapy at 90 days post discharge Vs Not discharged on warfarin and/or who did not fill a warfarin prescription within 90 days post-discharge.

All analyses were conducted by the Duke Clinical Research Institute.

RESULTS:

PATIENT AND IN-HOSPITAL CHARACTERISTICS:

PATIENT AND IN-HOSPITAL CHARACTERISTICS:

DAPT3,589

Triple T1,370

MI+AF+PCI 72.4% 27.6%

Male Or Female Female Male

H/o PCI or CABG, prior stroke, and recent AF or atrial flutter

Less frequent More frequent

On warfarin before admission Less frequent More frequent

In-hospital major bleeding event More frequent Less frequent

RESULTS

CHADS2 Score ATRIA Score

Warfarin Use Increased with Predicted stroke risk.

No association with Predicted bleeding risk.

RESULTS

PATIENT AND IN-HOSPITAL CHARACTERISTICS: DAPT3,589

Triple T1,370

Presented with STEMI Or NSTEMI STEMI NSTEMI

LVEF < 40% Or > 40% > 40% < 40%

Use of glycoprotein IIb/IIIa inhibitors during PCI Greater Use Bivalirudin

DES implantation for Primary PCI in STEMI No difference

DES implantation for Primary PCI in NSTEMI More likely Less likely

CLINICAL OUTCOMES

DAPT Triple T P Value

Unadjusted cumulative incidence rates of 2-year MACE

32.7% Vs 32.6% P=0.99

No difference

Unadjusted Cumulative incidence rates of 2-year MACE

CLINICAL OUTCOMES

DAPT Triple T P Value

Unadjusted cumulative incidence rates of 2-year MACE

32.7% Vs 32.6% P=0.99

No difference

Individual MACE component

All-cause mortality 24.8% 23.8% 0.70

Individual MACE component: All Cause Mortality

CLINICAL OUTCOMES

DAPT Triple T P Value

Unadjusted cumulative incidence rates of 2-year MACE

32.7% Vs 32.6% P=0.99

No difference

Individual MACE component

All-cause mortality 24.8% 23.8% 0.70

MI readmission 8.1% 8.5% 0.54

Individual MACE component: MI Readmission

Individual MACE component: Stroke Readmission

CLINICAL OUTCOMES

DAPT Triple T P Value

Unadjusted cumulative incidence rates of 2-year MACE

32.7% Vs 32.6% P=0.99

No difference

Individual MACE component

All-cause mortality 24.8% 23.8% 0.70

MI readmission 8.1% 8.5% 0.54

Stroke readmission 5.3% 4.7% 0.23

Individual MACE component: Ischemic Stroke

CLINICAL OUTCOMES

DAPT Triple T P Value

Unadjusted cumulative incidence rates of 2-year MACE

32.7% Vs 32.6% P=0.99

No difference

Individual MACE component

All-cause mortality 24.8% 23.8% 0.70

MI readmission 8.1% 8.5% 0.54

Stroke readmission 5.3% 4.7% 0.23

Ischemic Stroke 4.7% 3.2% 0.02

CLINICAL OUTCOMES Triple T Compared to DAPT P Value

Adjusted (patients, Rx and Hospital Ch.)Cumulative incidence rates of 2-year MACE

No differenceHR: 0.99 [95% CI: 0.86 to 1.16] p = 0.94

Individual MACE component

All-cause mortality HR: 0.98 [95% CI: 0.83 to 1.16] 0.82

MI readmission HR: 1.03 [95%CI: 0.79 to 1.33] 0.83

Stroke readmission HR: 0.85 [95% CI: 0.58 to 1.23] 0.38

Ischemic Stroke HR: 0.66 [95% CI: 0.41 to 1.06] 0.09

CLINICAL OUTCOMES AFTER ADJUSTMENTS:

BLEEDING OUTCOMES Unadjusted

DAPT Triple T P Value

Cumulative incidence rates of Bleeding requiring Hospitalization in 2 yr

11.0% 17.6% < 0.0001

BLEEDING OUTCOMES: According to Triple T. Vs DAPT

BLEEDING OUTCOMES After Adjustment

Triple T Compared to DAPT

Cumulative incidence rates of Bleeding requiring Hospitalization in 2 yr

HR: 1.61 [95% CI: 1.31 to 1.97] p < 0.0001

BLEEDING OUTCOMES Unadjusted

DAPT Triple T P Value

Cumulative incidence rates of Bleeding requiring Hospitalization in 2 yr

11.0% 17.6% < 0.0001

Intracranial Hemorrhage 1.5% 3.4% < 0.0001

BLEEDING OUTCOMES After Adjustment

Triple T Compared to DAPT

Cumulative incidence rates of Bleeding requiring Hospitalization in 2 yr

HR: 1.61 [95% CI: 1.31 to 1.97] p < 0.0001

Intracranial Hemorrhage HR: 2.04 [95% CI: 1.25 to 3.34]p < 0.01

SECONDARY ANALYSIS:

Total Patients with Medicare part D prescription coverage before discharge Discharged on warfarin Discharged on DAPT only

1,591 72.2% (424) 27.8% (1,149)

Rates of warfarin persistence at 3 months 93.2% (n . 412)

Rates of P2Y12 inhibitor persistence 94.7% (n . 1,088)

Post discharge antithrombotic medication persistence:

Filled warfarin prescription within 90 days

Not Discharged on warfarin 11.4% (n . 232)

Of 425 with CHADS2 score >2 + Not Discharged on warfarin 12.7% (n. 54)

LANDMARK ANALYSIS: Starting 90 days post discharge

Persistently on warfarin Vs Not discharged with + did not fill warfarin prescription

Risk of MACE - Similar adjusted HR: 0.96 [95% CI: 0.67 to 1.36] p . 0.81

Higher trend for Risk of bleeding adjusted HR: 1.50 [95% CI: 0.92 to 2.46] p . 0.10

Use triple therapy for as short a time as possible + Careful consideration of stroke, thrombosis, and bleeding risk.

27.6% of older MI+AF+PCI = Triple therapyProportion increased with the estimated stroke risk and did not vary with the predicted bleeding risk.

Current practice guidelines:

DISCUSSION:

National registry data from 2007 to 2010 from >400 U.S. hospitals to identify large cohort MI+AF+PCIOne of the largest studies

Focused on older population - Highest risk of thrombotic events but also of bleeding events. Large sample size + high risk population permitted good statistical power

Had access to detailed clinical information, treatment and events - include these variables in risk-adjusted models.

Medicare Part D data - to examine post-discharge warfarin persistence or initiation - added insight to findings

STRENGTHS:Adds to the literature in several ways:

Method of AF identificationMedicare and registry data - Not validatedDifferences in the data source for AF diagnosis between groups could result in bias.

Observational StudyUnmeasured confounders - No data regarding provider rationale for treatment choices (e.g., timing, type, or duration of AF; patient bleeding risk; upcoming invasive procedures)Selection bias persists despite adjustment.

Significant postdischarge treatment crossoverlarge drop in the proportion of patients taking warfarin between 6 and 12 months.

May mask potential associations between warfarin use and outcomes

Multiple factors:Uncaptured bleeding eventsReassessment of fall risk in this older populationMedication discontinuation for proceduresDifficulty with INR monitoring

STUDY LIMITATIONS:

Only included bleeding event requiring hospitalizationBleeding of lesser severity - Outpatient treatment and evaluation

Did not have adequate sample size to compare combinations of antithrombotic therapies other than Triple T versus DAPT

Could not assess novel oral anticoagulant agents

Could not use the HAS-BLED OR HEMORR2HAGES bleeding score

Analysis focused on older patients

STUDY LIMITATIONS

CONCLUSIONS:

One of the largest studies

¼ discharged on triple therapy

Triple therapy use increased with predicted stroke risk but not with bleeding risk

Use of triple therapy Not associated with a lower 2-year risk of mortality or MACE.Associated with a significantly higher early and long-term risk of bleeding, including intracranial hemorrhage.Association was persistent among subgroups.

LINKED

Mechanism of Action - P2Y12 Receptor Antagonists Mechanism of action of the P2Y12 antagonists.

P2Y1 and P2Y12 are G-coupled receptors which utilize ADP as an agonist.

P2Y1 (Gq-coupled receptor) - Stimulation of PLC and phosphatidylinositol-signaling pathway.

P2Y12 (Gi-coupled 7-transmembrane domain receptor)

❏ Inhibits an AC-mediated signaling pathway and decreases the cAMP intracellular levels.

❏ Inhibits PI3K and induces Akt kinase activation.

Decrease in cAMP

❏ Reduces the rate of phosphorylation of VASP

❏ Activation of the GPIIb/IIIa receptor and platelet aggregation.

AC: Adenyl cyclase;

PLC: Phospholipase C;

VASP: Vasodilator-stimulated phosphoprotein;

VASP-P: Vasodilator-stimulated phosphoprotein phosphorylation.

Return

History of AF or atrial flutter

Considered to be present

During the 2 weeks before the MI admission - ACTION Registry–GWTG data collection form

ICD-9 code 427.3x - inpatient or outpatient encounter billing record - 1 year before index MI hospitalisation

Return

HAS-BLED

Return

HEMORR2HAGES

Return

HEMORR2HAGES – The HEMORR2HAGES score was created by combining risk factors from existing scoring systems [19]. Each factor is assigned 1 point, with the exception of a previous bleeding episode (2 points):

•Hepatic or renal disease

•Ethanol abuse

•Malignancy

•Older age (>75 years)

•Reduced platelet count or function, including aspirin therapy

•Rebleeding risk (history of prior bleed)

•Hypertension

•Anemia

•Genetic factors

•Excessive fall risk

•Stroke

Risks of major bleeding per 100 patient-years were 1.9 (0 points), 2.5 (1 point), 5.3 (2 points), 8.4 (3 points), 10.4 (4 points), and 12.3 (≥5 points).