dapt trial - cdn.ymaws.com · to determine whether dual antiplatelet therapy (dapt) beyond 12...

7/24/2015

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49th Annual Meeting

OWNING CHANGE: Taking Charge of Your Profession

TOP PAPERSCardiac/Vascular

Christine Price, Pharm.D.Clinical Coordinator

PGY1 Residency Director

Disclosure

I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation

Honorarium and travel expenses donated to FSHP

Objectives

To determine whether dual antiplatelet therapy (DAPT) beyond 12 months is associated with reduction in stent thrombosis and/or major cardiovascular and cerebrovascular events.

To determine the impact of DAPT therapy beyond 12 months on moderate or severe bleeding.

To assess the prevention of thrombotic events with ticagrelor compared to placebo on a background aspirin therapy in patients with a history of myocardial infarction.

To compare angiotensin neprilysin inhibition with enalapril to determine the impact on global mortality and morbidity in heart failure patients.

DAPT Trial

Background

Millions of patients worldwide receive coronary stents for the treatment of ischemic heart disease

Current guidelines recommend 1yr of DAPT

Several, underpowered studies debated length of therapy

The DAPT study was designed from a request from the FDA to evaluate the effects of DAPT with stents beyond 1yr

Background

?

Reduce Thrombus FormationReduce Thrombus Formation Increase Bleeding RiskIncrease Bleeding Risk

< 12 months > 12 months

EXCELLENT ARTIC‐Interruption

OPTIMIZE DES‐LATE

RESET Hu et al.

SECURITY REAL/ZEST

ISAR‐SAFE DAPT

PRODIGY; ITALIC

Is Shorter Better Is Longer Better

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Background

Meta-analysis: Shorter Duration

Risk of Myocardial Infarction Risk of Major Bleeding

Primary Efficacy End Points

Two Powered Co-primary Effectiveness Endpoints:

Clinical: Major adverse cardiovascular and cerebrovascular events (MACCE) within the 12-30 month period

defined as the composite of death, MI or stroke

Stent Thrombosis: Incidence definite/probable stent thrombosis (ST) within the 12–30 month period

Academic Research Consortium (ARC) definition

Primary Safety End Points

Moderate or Severe Bleeding GUSTO criteria Severe or life-threatening: Either intracranial hemorrhage or bleeding that

causes hemodynamic compromise and requires intervention

Moderate: Bleeding that requires blood transfusion

BARC criteria (Bleeding Academic Research Consortium) Type 0: No bleeding

Type 1: Bleeding that is not actionable and doesn’t require treatment

Type 2: Actionable sign of hemorrhage (nonsurgical, medical intervention; hospitalization or increased level of care)

Type 3: (a) bleeding with Hgb drop 3 to <5g/dL; (b) HgB drop ≥ 5g/dl; (c) Intracranial or Intraocular

Type 4: CABG-related bleeding

Type 5: (a) Probable fatal bleeding; (b) Definite fatal bleeding

Methods: Study Design

International, Multicenter, Randomized, Placebo Controlled

IRB approved

FDA and a public-private collaboration Pharmaceutical and 8 coronary stent manufacturers

Funded the study

Contributing roles in design of the trial and data collection

Harvard Clinical Research Institute (HCRI)

Responsible for scientific conduct

Independent analysis of the data

Methods: Study Population

11 Countries, 452 Sites

> 18 years of age

Percutaneous intervention (PCI) with stent (or within 3 calendar days)

Receiving clopidogrel 75mg daily or prasugrel 10mg daily or 5mg daily if <60kg in combination with

Aspirin 75 to 162mg daily

No contraindicationd to DAPT for at least 30 months after enrollment

Index procedure stent placement with stent diameter <2.25 mm or >4.0 mm.

Pregnant women

Planned surgery requiring discontinuation of therapy (>14 days) during the 30 mo

Life expectancy of less than 3 years

Enrollment in another device or drug study

Concurrent anticoagulant therapy

Hypersensitivity or allergies to one of the drugs or devices

Subject treated with both DES and BMS during the index procedure

Enrollment Inclusion Criteria Enrollment Exclusion Criteria


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Randomization Treatment Ends

18 months additional treatment18 months additional treatment

Randomized: Free from MI, Stroke, repeat revascularization, moderate or severe bleeding and compliant (80-120% of doses taken, no interruption >14days).

Statistical Analysis

Sample Size Primary Efficacy: 9800 patients

ST and MACCE Assumptions

Annual event rates for placebo

Hazard Ratio (HR) with continued thienopyridine vs placebo

Provided 85% power for superiority

Primary Safety: 9960 patients

Farrington-Manning Risk Difference:

Annual rate of moderate to severe bleed

Absolute noninferiority margin of 0.8%; One-sided alpha = 0.025

Provided 80% power to detect noninferiority


Primary Efficacy

Kaplan-Meier Estimates

Intention-to-treat, cumulative incidence of each end point

Primary Safety

Primary Noninferiority Assessment

Completed 17 months or bleeding event

Procedure Characteristics

Thienopyridine Placebo(N=5020) (N=4941)

N Engl J Med 2014;371:2158

Drug-eluting Stent at Index ProcedureResults: Efficacy

Results: Efficacy

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Results: Efficacy Results: Efficacy

Results: SafetyAdditional Analyses

Additional Analysis: Stent Thrombosis

Overall N=9961

Additional Analysis: MACCE

Overall N=9961

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Additional Analysis: MI

Overall N=9961

Limitations

Patient’s were lower risk for late events

Net effect of ischemic and bleeding events not quantified A decision analysis suggested that small absolute differences in the

rates of cardiovascular events may be sufficient to counterbalance bleeding risks

No randomization to specific drug or stent

Included 1st generation stents

Aspirin doses varied

Higher mortality (cancer)

Unknown GI ppx with PPIs

Who will benefit? And Costs to patient?

Discussion

For Every 1000 patients on DAPT up to 30 months

Conclusion

DAPT beyond 1 year after placement of a DES, vs. aspirin therapy alone, significantly reduced the risks of ST and MACCE events

Associated with an increased risk of bleeding

PEGASUS-TIMI 54 Background

MI affects nearly 8 million people in the U.S.

Prior MI risk for subsequent ischemic events

Current guidelines recommend adding a P2Y12 receptor antagonist to aspirin only for the first year after an acute coronary syndrome (ACS)

Optimal duration of DAPT after MI, however, is not known

Landmark analyses from 1 year ACS trials showed benefit

Post-hoc MI subgroup analysis from CHARISMA

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International, Multicenter, Randomized, Placebo Controlled

IRB approved

Trial collaboration

TIMI Study Group Conducted all data analysis independently of the sponsor Clinical end points and bleeding events Members unaware of treatment assignments

Sponsor: AstraZeneca Executive and Steering Committees Independent Data Monitoring Committee



Age ≥50 years

At least 1 of the following:

Age ≥65 years

Diabetes requiring medication

2nd prior MI (>1 year ago)

Multivessel CAD

CrCl <60ml/min

Tolerating ASA and able to be dosed at 75-150 mg/d

Planned use of P2Y12 antagonist, dipyridamole, cilostazol, or anticoag

Planned revascularization

CABG in the past 5 years

Bleeding disorder

History of ischemic stroke, ICH, CNS tumor or vascular abnormality

Recent GI bleed or major surgery

At risk for bradycardia

Dialysis or severe liver disease

Strong CYP3A inhibitors, inducers, substrates with narrow indices

Inclusion Criteria Exclusion Criteria


Efficacy End Points

Primary Composite Endpoints Cardiovascular(CV) death, MI, Stroke

Secondary Endpoints CV death

All-cause mortality

Prespecified Exploratory Death from CAD, MI, Stroke

Individual components of the composite end points

Urgent coronary revascularization

Hospitalized for unstable angina and TIA

Safety End Points

Primary Endpoints TIMI Major Bleeding Any intracranial bleeding OR Fatal bleeding OROvert signs of hemorrhage with Hgb drop of ≥5 g/dl

Other Safety Endpoints TIMI Minor BleedingOvert signs of hemorrhage with Hgb drop of 3 to <5 g/dl

TIMI Minimal Bleeding

Bleeding requiring transfusion, intervention or hospitalization

Intracranial hemorrhage (ICH), Fatal bleeding

Adverse events

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Sample Size: 21,000 patients

1360 primary endpoint events needed

90% power to detect 20% RRR of 90mg dose

83% power to detect 19% RRR of 60mg dose

Based on CHARISMA and DISPERSE trials

Controlled for Type I error of 5%

Kaplan-Meier estimates of cumulative incidences at 36 mo

Cox proportional hazards model generated HR and 95% CI

Two sided p values

Follow Up

Ticagrelor 90mg bid

(N=7050)

Premature discontinuation

(32%)

Died during follow up

(4.7%

Withdrew(0.7%)

Ticagrelor 60mg bid

(N=7045)


(29%)


(4.2%

Withdrew(0.7%)

Placebo(N=7067)


(21%)


(4.7%

Withdrew(0.7%)

Randomized (N = 21,162)

P<0.001

Baseline Characteristics

No difference between treatment arms.

%


No difference between treatment arms.

%

Results: Efficacy

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Results: Safety

Results: Safety

Adverse EventTicagrelor90 mg bid(N=6988)

Ticagrelor60mg bid(N=6958)

Placebo(N=6996)

Ticagrelor 90mg vs Placebo

Ticagrelor 60mg vs Placebo

3-yr KM rate % P-value P-value

Bleeding requiringtransfusion

2.4 2.1 0.7 <0.001 <0.001

Bleeding leading to study-drug d/c

7.8 6.2 1.5 <0.001 <0.001

Dyspnea 18.9 15.8 6.4 <0.001 <0.001

• Leading to study-drug d/c

6.5 4.6 0.8 <0.001 <0.001

• Severe 1.2 0.6 0.2 <0.001 <0.001

Bradyarrhythmia 2.0 2.3 2.0 0.31 0.10

Gout 2.3 2.0 1.5 <0.001 0.01

Discussion

Showed a 15% lower risk of MI, Stroke or CV death

Efficacy of 90mg and 60mg were virtually the same

2.3-2.6 fold higher risk of clinically significant bleeding

3-3.7 fold higher risk of transfusion

3 fold increase risk of dyspnea

30% discontinuation rate

Generalizability to other populations? Stable, prior ACS patients (MI about 2 yrs prior)

Excluded recent bleeding, stroke or anticoagulant need

Costs to patient?

Conclusions

Long-term DAPT with low-dose aspirin and ticagrelor should be considered in appropriate patients with a MI

The 60mg dose has similar efficacy with less bleeding and side effects Offers a more attractive benefit-risk profile

For every 10,000 patients treated: 90mg prevented 40 primary events but had 42 TIMI major bleeds

60mg prevented 40 primary events but had 31 TIMI major bleeds

PARADIGM-HF

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Background

About 5.1 million Americans have heart failure

>650,000 new cases/year

New cases increasing due to increased survival post MI

~20% lifetime risk ≥40 years of age

Mortality rate

50% overall 5-year survival for all patients

<65 yrs; 80 % men and 70% women die within 8 yrs

Most common reason of hospitalization in US > 65yo

2013 ACC/AHA HF guidelines: ARBs if intolerant to ACEIs

Background

MedicationDecrease

Mortality (HFrEF)Improved

Symptoms/QOL

ACE-Inhibitors Yes Yes

ARB valsartan/candesartan

Yes Yes

Beta Blockers Yes Yes

Hydralazine-isosorbide dinitrate

Yes Yes

Aldosterone antagonist Yes Yes

Digoxin No Yes

Diuretics No Yes

LCZ696

LCZ696: Angiotensin Receptor Neprilysin Inhibition

Angiotensinreceptor blocker

Inhibition of neprilysin

Background

Valsartan Sacubitril

Endogenousvasoactive peptides

(natriuretic peptides, adrenomedullin,bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neprilysin

Neprilysininhibition

Background

• Counters neurohormonal activation

• Vasodilation

• Decrease sodium retention

• Decrease remodeling

10,521 patients screened at1043 centers in 47 countries

8399 patients randomized for ITT analysis

LCZ696 (n=4187)

200 mg bid

Enalapril (n=4212)

10 mg bid

median 27 monthsof follow-up

Methods: Study Designtient Disposition

Double-blind

1:1


Study Oversight Executive Committee Design and Conduct of trial

Data analysis (collaboration with sponsor)

Independent data and safety monitoring committee

Sponsor, Novartis Data collection and analysis

Makers of valsartan (Diovan®) and sacubitril

Independent academic statician Replicated analysis

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Single-blind Run-in Period:

Enalapril 10mg bid x 2 weeks

Single-blind Run-in Period:

LCZ696 100mg bid x 1-2 weeks

LCZ696 200mg bid x 2-4 weeks

Double-blind Treatment PeriodLCZ696 200mg bid vs Enalapril 10mg bid

10.5% dropout

10.4% dropout

At least 18 yr

NYHA class II, III, IV

Ejection Fraction ≤40% (≤35%-changed 12/10)

NT-proBNP ≥600 pg/ml (≥400 if recently hospitalized)

BNP ≥ 150 pg/ml (≥100 if recently hospitalized)

ACE or ARB/BB use equivalent to enalapril 10mg 4 wks prior

Symptomatic hypotension

SBP ≤ 100 mmHg

eGFR <30 ml/min

Serum K ≥ 5.2 mmol

Hx of angioedema or side effect from ACEI or ARB use

Acute decompensated HF

CVA, ACS, Vent arrhythmia or CRT within previous 3 months

Inclusion Criteria Exclusion Criteria


Primary Outcome Composite of death from cardiovascular causes or

hospitalizations for heart failure

Powered to detect differences in CV death

Secondary Outcomes All-cause mortality

Change from baseline in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 8 months

Time to new onset of atrial fibrillation

Time to first occurrence of decline in renal function

Study Outcomes Statistical Analysis

Assumed annual rate of cardiovascular death ~14.5%

Assumed annual rate CV death in enalapril ~7%

8000 patients to achieve power of 80% for CV death

Target relative risk reduction ~15%


LCZ696(n=4187)

Enalapril(n=4212)

Age (years) 63.8 ± 11.5 63.8 ± 11.3

Women (%) 21.0% 22.6%

LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3

NYHA functional class I 4.3% 5%

NYHA Functional Class II 71.6% 69.3%

NYHA Functional Class III 23.1% 24.9%

NYHA Functional Class IV 0.8% 0.6%

Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15

B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465)

History of diabetes 35% 35%

Digitalis 29.3% 31.2%

Beta-adrenergic blockers 93.1% 92.9%

Mineralocorticoid antagonists 54.2% 57.0%

ICD / CRT 14.9 / 7% 14.7 / 6.7%

0

16

32

40

24

8

Enalapril(n=4212)

360 720 10800 180 540 900 1260

Days After Randomization

41874212

39223883

36633579

30182922

22572123

15441488

896853

249236

LCZ696Enalapril

Patients at Risk

1117

Kap

lan

-Mei

er E

stim

ate

of

Cu

mu

lati

ve R

ates

(%

)

914

LCZ696(n=4187)

HR = 0.80 (0.73-0.87)P = 0.0000002

Number needed to treat = 21

Results: Primary Outcome

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Enalapril(n=4212)

LCZ696(n=4187)

HR = 0.80 (0.71-0.89)P = 0.00004

Number need to treat = 32

Kap

lan

-Mei

er E

stim

ate

of

Cu

mu

lati

ve R

ates

(%

)

Days After Randomization

41874212

40564051

38913860

32823231

24782410

17161726

1005994

280279

LCZ696Enalapril

Patients at Risk

360 720 10800 180 540 900 12600

16

32

24

8

693

558

Results: Cardiovascular DeathResults

Limitations

Trial was stopped early

Dosing equivalence

Max dose of valsartan but half for enalapril

Trial design with run-in periods Tested enalapril to LCZ696 but not visa versa until enrollment

Meant to “filter” patients who are tolerant to medication

Can this population be reproducible?

Comparison of LCZ696 to valsartan alone

Difference in Digitalis/mineralocorticoid antagonist use

Conclusions

“Angiotensin receptor-neprilysin inhibition with LCZ696 was superior to ACEI alone in reducing the risks of death and hospitalization for heart failure. “

References

1. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of Dual Antiplatelet Therapy (DAPT) after Drug-Eluting Stents. NEJM2014 371;23:2155-66.

2. Bonaca MP, Bhatt DL, Braunwald E, et al. Design and rationale for the Prevention of Cardiovascular Events in Patients With PriorHeart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial. Am Heart J 2014;167:437-44.

3. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. NEJM 2015;372(19):1791-1800.

4. Gilard M, Barragan P, Noryani AA, et. al. 6 Versus 24-Month Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents in Patients Nonresistant to Aspirin. ITALIC Trial. JACC 2015;65(8):777-86.

5. Gwon HC, Hahn JY, Park KW, et al. Six- month vs. 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Vs. Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012;125:505–13.

6. Feres F, Costa RA, Abizaid A, et al. Three vs. twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013;310:2510–22.

7. Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). JACC 2012;60:1340–8.

8. Collet JP, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomized trial. Lancet 2014 July 15.

9. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial PRODIGY. Circulation 2012;125:2015-26.

10. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events NEJM 2006;354:1706-17.

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References

11. Husted S, Emanuelsson H, Heptinstall S, et. al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27:1038-47.

12. McMurray J, Packer M, Desai AS, et. al. PARADIGM-HF: Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. NEJM2014;371(11):993-1003.

13. Effect of Candesartan on Cause-Specific Mortality in Heart Failure Patients: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity(CHARM) Program Circulation. 2004;110:2180-2183.

14. Cohn JN, Tognoni GA. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. NEJM 2001;345:1667-75.

15. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).NEJM 1987;316:1429-35.

16. ACCF/AHA Practice Guideline: 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College ofCardiology Foundation/American Heart Association Task Force on Practice Guidelines Clyde W. Yancy, Mariell Jessup, Biykem Bozkurt, Javed Butler, Donald E. Casey, Jr, Mark H. Drazner, Gregg C. Fonarow, Stephen A. Geraci, Tamara Horwich, James L. Januzzi, Maryl R. Johnson, Edward K. Kasper, Wayne C. Levy, Frederick A. Masoudi, Patrick E. McBride, John J.V. McMurray, Judith E. Mitchell, Pamela N. Peterson, Barbara Riegel, Flora Sam, Lynne W. Stevenson, W.H. Wilson Tang, Emily J. Tsai, and Bruce L. Wilkoff Circulation. 2013;128:e240-e327, published online before print June 5 2013, doi:10.1161/CIR.0b013e31829e8776

17. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task force on Practice Guidelines. Circulation 2014;130:2354-94.

18. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127(4):e362-e425. [Erratum, Circulation 2013;128(25):e481.]

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dapt trial - cdn.ymaws.com · to determine whether dual antiplatelet therapy (dapt) beyond 12...

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