Post on 05-Jun-2020
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
Methods: Study Population
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Methods: Study Population
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
Statistical Analysis
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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Methods: Study Design
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
Methods: Study Design
Methods: Study Population
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
Methods: Study Population
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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Statistical Analysis
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)
Premature discontinuation
(29%)
Died during follow up
(4.2%
Withdrew(0.7%)
Placebo(N=7067)
Premature discontinuation
(21%)
Died during follow up
(4.7%
Withdrew(0.7%)
Randomized (N = 21,162)
P<0.001
Baseline Characteristics
No difference between treatment arms.
%
Baseline Characteristics
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
Methods: Study Design
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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Methods: Study Design
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
Methods: Study Population
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%
Baseline Characteristics
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.]
QUESTIONS ?