TOPCAT ACCP Cardiology PRN Journal Club Presentation

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ACCP Cardiology PRN Journal Club 1

Transcript of TOPCAT ACCP Cardiology PRN Journal Club Presentation

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ACCP Cardiology PRN Journal Club

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Announcements • Thank you attending the ACCP Cardiology PRN Journal Club– Thank you if you attended before or have been attending

• I have created a PB Works Site that will house our recorded calls, handouts, and Summary/Q&A documents. The link is https://accpcardsprnjournalclub.pbworks.com/

• If there are any suggestions, please let us know.

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Ezetimibe Added to Statin Therapy after Acute Coronary Syndrome (IMPROVE-IT)

Kyle Thorner, Pharm.D.PGY2 Cardiology Resident

WakeMed Health & HospitalsRaleigh, NC

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Disclosure Statement

Kyle Thorner has no conflicts of interest to disclose.

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Background• Ezetimibe inhibits the absorption of LDL-C

from the intestinal lumen via inhibition of Niemann-Pick C1 (NPC1L1).

NEJM 2014;371:2072-82Science 2004;303:(5661):1149

• Mutations in NPC1L1 reduce plasma LDL-C and have been associated with reduced risk of CHD

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Background

• Prior clinical trial experience with ezetimibeTrial Treatment Primary Outcome Result

ENHANCESimvastatin/Ezetimibe

80/10 mg vs Simvastatin 80 mg

Mean Δ carotid-artery intima-media thickness

0.0058 mm vs 0.0111 mm, p=0.28

SEAS Simvastatin/Ezetimibe 40/10 mg vs Placebo

Composite of major cardiovascular events

35.5% vs 38.2%; HR 0.96 (0.83-1.12),

p=0.59*

SHARP Simvastatin/Ezetimibe 20/10 mg vs Placebo

First major atherosclerotic event

13.4% vs 11.3%; RR 0.83 (0.74-0.94),

p=0.0021

NEJM 2008;358(14):1431-1443NEJM 2008;359:1343-1356Lancet 2011;377:2181-2192

*Incidence of cancer: 105 vs 70, p=0.01

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IMPROVE-IT Study Objective

To evaluate the effect of ezetimibe combined with simvastatin, as compared with that of

simvastatin alone, in stable patients who had had an acute coronary syndrome and whose LDL

cholesterol values were within guideline recommendations.

NEJM 2015;372(25):2387-2397

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Study PopulationInclusion Criteria Exclusion Criteria

- Age ≥ 50 years- Hospitalization within

previous 10 days for ACS- LDL cholesterol ≥ 50 mg/dL- LDL ≤125 mg/dL for patients

naïve to lipid-lowering therapy

- LDL ≤100 mg/dL for patients on lipid-lowering therapy

- Planned CABG- CrCl < 30 ml/min- Active liver disease- Use of statin therapy with

LDL-lowering potency greater than 40 mg of simvastatin

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Study Design• International, multi-center, double-blind, placebo-controlled,

randomized trial

• Follow-Up– Visits: At 30 days, 4 months and every 4 months thereafter– Blood Samples: at randomization, at 1, 4, 8, and 12 months, and

then yearly

18,144 patients

Simvastatin 40* mg + Placebo daily

(n=9077)

Simvastatin 40* mg + Ezetimibe 10mg daily

(n=9067)

*Simvastatin could be uptitrated to 80 mg if

LDL-C >79 mg/dL, addendum made after FDA advisory in 2011

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Study EndpointsPrimary Endpoint• Composite of death from CVD, major coronary

event, or nonfatal stroke

Safety Endpoints• Liver enzyme levels• CK levels• Episodes of myopathy or rhabdomyolysis• Gallbladder-related adverse events• Cancer

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Statistics & Enrollment

Statistics Enrollment• N = 18,144• Median follow-up = 6 years• Total follow-up = 7 years• Regions:

– North America (N=6,973)– Western Europe (N=7,274)– Eastern Europe (N=1,416)– Asia Pacific (N=896)– South America (N=1,585)

• Estimated that 5,250 events required for 90% power to detect a 9.375% lower relative risk for the primary end point with simvastatin-ezetimibe vs simvastatin

• Intention-to-treat analysis

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Variable Simvastatin(n=9077)

Simvastatin-Ezetimibe(n=9067)

Mean Age, yrs 63.6 63.6Male Sex, % 75.9 75.5White Race, % 84 83.6Mean LDL, mg/dL 93.8 93.8Index EventSTEMI / NSTEMI / UA, % 28.7 / 46.9 / 24.4 28.5 / 47.5 / 24PCI, % 69.7 70.5Medications prior to index ACSStatin, %Aspirin, %

34.342.5

35.641.9

Medications post ACSAspirin, %Thienopyridine, %Beta Blocker, %ACE-Inhibitor or ARB, %

96.986.186.875.8

97.186.687.375.3

Baseline Characteristics

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Results1 Yr Mean LDL-C TC TG HDL hsCRPSimva 69.9 145.1 137.1 48.1 3.8

EZ/Simva 53.2 125.8 120.4 48.7 3.3

Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5

Simva

EZ/Simva

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Results

Total NNT= 50Yearly NNT= 350

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ResultsTertiary Outcomes Simvastatin

(n=9077)Simvastatin-

Ezetimibe (n=9067)

HR(95% CI)

p-Value(NNT)

Nonfatal MI 1083 (14.4%) 945 (12.8%) 0.87 (0.8-0.95)

0.002(63)

Ischemic Stroke 297 (4.1%) 236 (3.4%) 0.79(0.67-0.94)

0.008(143)

Safety Outcomes Simvastatin(n=9077)

Simvastatin-Ezetimibe (n=9067)

p-Value

ALT, AST, or both ≥3 ULN 208 (2.3%) 224 (2.5%) 0.43

Rhabdomyolysis 18 (0.2%) 13 (0.1%) 0.37

Myopathy 10 (0.1%) 15 (0.2%) 0.32

Cancer 732 (10.2%) 748 (10.2%) 0.57

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Author’s Conclusion

The addition of ezetimibe to statin therapy in stable patients with recent ACS and who had LDL cholesterol levels within guideline recommendations further lowered the risk

of cardiovascular events.

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Study CritiqueStrengths

• Large sample size with long duration of follow-up

• Low incidence of adverse effects with simvastatin/ezetimibe

• Age subgroup analysis comparable to modern guidelines

Weaknesses

• Intensity of statin therapy does not reflect current guideline recommendations

• Amount of study drug discontinuation

• Modest benefit and primarily in nonfatal endpoints

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Impact on Clinical Practice• First clinical trial to show benefit on composite CV

outcome when adding non-statin therapy to a statin.Trial Treatment Primary Outcome Result

The ACCORD Study Group

Simvastatin + Fenofibrate/Placebo

Nonfatal MI/Nonfatal stroke/CV death

HR 0.92 (0.79-1.08) P=0.32

AIM-HIGH Simvastatin +/- Ezetimibe + Niacin/Placebo

Nonfatal MI/Ischemic Stroke/ACS hospitalization/Revascularization/CV death

Stopped early due to lack of efficacy

HPS2-THRIVE Simvastatin +/- Ezetimibe + Niacin/Placebo

Time to first major vascular event

RR 0.96 (0.90-1.03)P=0.29

The dal-OUTOMES

Investigators

Dalcetrapib vs placebo in addition to standard of

care (98% statins)

CHD death, nonfatal MI, ischemic stroke, unstable

angina, cardiac arrest

HR 1.04, (0.93-1.16)P=0.52

NEJM 2010;362(17):1563-1574, NEJM 2011;365(24):2255-2267NEJM 2014;371(3):203-212, NEJM 2012;367(22):2089-2099

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Impact on Clinical Practice• May support the LDL hypothesis, but does not disprove

the statin hypothesis.– Reconsider LDL-C targets in future guidelines– Future study: High intensity statin compared to

ezetimibe/simvastatin with equal LDL lowering

• Could apply results to justify addition of ezetimibe to moderate intensity statin therapy– Patients intolerant of high-intensity statins– Elderly patients– Diabetic patients

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Acknowledgements

• Dave L. Dixon, Pharm.D., AACC, FNLA, CDE, CLS, BCPS-AQ Cardiology– Virginia Commonwealth University School of Pharmacy

• Erin (Allender) Ledford, Pharm.D., BCPS-AQ Cardiology– WakeMed Health & Hospitals

• Janna Beavers, Pharm.D., BCPS– WakeMed Health & Hospitals

• Craig Beavers, Pharm.D., AACC, BCPS-AQ Cardiology– TriStar Centennial Medical Center

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Thank you for attending!

• If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at [email protected] or [email protected]

• Join us next month when we hear the BRIDGE Trial from Leah Sabato, PharmD PGY-2 Cardiology from Vanderbilt with Michael Gulseth , PharmD as mentor