ACCP Cardiology PRN Journal Club

Presenter: Sarah Schaidle

Dr. Schaidle is a PGY2 Cardiology Pharmacy Resident at the University of Kentucky. She graduated from the University of Colorado School of Pharmacy and completed her PGY1 Pharmacy Resident at Northwestern Memorial Hospital. Her current practice interests include acute care cardiology and academia. After residency, Dr. Schaidle plans to obtain a position as an inpatient cardiology pharmacist.

Effects of n-3 Fatty Acid Supplements in Diabetes

Mellitus:ASCEND Trial

Sarah Schaidle, PharmDPGY2 Cardiology Pharmacy ResidentUniversity of Kentucky HealthCare

October 31st, 2018

Disclosure Statement

The speaker has no actual or potential conflicts of interest to disclose.

Omega-3 Fatty Acids

Omega-3 Polyunsaturated Fatty Acids

Plant-Derived α-linolenic (LNA)

Marine-Derived

Eicosapentaenoic acid (EPA)

Docosahexaenoic acid (DHA)

AHA Recommendations for Omega-3 Fatty Acids

1996• Evidence for beneficial effects of n-3 fatty acids is either lacking or needs

additional study

2002• Patients without documented coronary heart disease (CHD) should eat a

variety of fish at least twice a week, but omega-3 fatty acid supplementation should be considered in patients with documented CHD

2017• Omega-3 fatty acids are reasonable only for the secondary prevention of

CHD and sudden cardiac death among patients with prevalent CHD and secondary prevention of outcomes in patients with heart failure

Circulation. 1996 Nov 1;94(9):2337-40.Circulation. 2002 Nov 19;106(21):2747-57.

Circulation. 2017 Apr 11;135(15):e867-e884.

ESC Recommendations for Omega-3 Fatty Acids

• 2016 European Guidelines on Cardiovascular Disease Prevention in Clinical Practice• Routine use of omega-3 fatty acids is not recommended in CVD

prevention given limited evidence to supports its use• Recommend healthy diet consisting of fish 1–2 times per week

European Heart Journal (2016) 37, 2315–2381.

ASCEND Study Objective

To assess the efficacy and safety of daily supplementation with n-3 fatty acids, as

compared with placebo, in patients with diabetes without evidence of cardiovascular disease

Study Population

Inclusion Criteria Exclusion Criteria

Men and women ≥ 40 years old Clear indication or contraindicationfor the receipt of n-3 fatty acids

Diagnosis of diabetes mellitus (any type) without evidence of cardiovascular disease

Other condition that might limit adherence to at least 5 years of participation in the trial

Study Design

• Randomized, two-by-two factorial study • Aspirin versus placebo• Omega-3 fatty acid versus placebo

• Randomization• 1 gram capsule (840 mg) marine n-3 fatty acids once daily• 460 mg of EPA• 380 mg of DHA

• 1 gram placebo capsule (olive oil)

Patient Selection and Enrollment

Identification

• Regional diabetes registers or general practice data from around the United Kingdom

Questionnaire

• If returned indicating they were willing and eligible to participate

Run-In Phase

• 8-10 week run-in period to assess for adherence

Eligibility

• Returned survey that confirmed their willingness to continue and adherence to the trial regimen

Outcomes

Primary Outcome• Serious vascular event (SVE), defined as composite of

nonfatal myocardial infarction, stroke, transient ischemic attack (TIA)*, or vascular death

Secondary Outcome• Composite of any SVE or any arterial revascularization

procedure

*TIA added during recruitment phase to increase the statistical power of the trial

Statistics and Enrollment

Statistics• 7.5 years of scheduled treatment

required to detect a relative between-group difference in SVE of 15%• Based on SVE rate of 1.2-1.3%

per year• Power à 90%

• Intention-to-treat analysis• Time-to-event analysis

Enrollment• N=15,480• Mean follow-up = 7.4 years• Complete follow-up data was

available for 99.1% of patients• Mean adherence

• 77% in fatty acid group• 76% in placebo

Baseline Characteristics

63.3 ± 9.2 years (mean)Age

62.6%Male sex

96.5%White race

30.7 ± 6.3 (mean) BMI7 years (median)Duration of DM

Aspirin 35.6%, Statin 75.3%Medication Use

Low 40.5%, Moderate 42.3%, High 17.2%Vascular Score

Primary Outcome – First Serious Vascular Event

Fatty Acids(N=7740)

Placebo(N=7740)

Rate Ratio (95% CI) P Value

No. of patients (%) 689 (8.9%) 712 (9.2%) 0.97 (0.97-1.08) 0.55

Secondary OutcomesOutcome

No. of patients (%)Fatty Acids(N=7740)

Placebo(N=7740)

Rate Ratio (95% CI)

SVR or revascularization 882 (11.4%) 887 (11.5%) 1.00 (0.91-1.09)All-cause Mortality 752 (9.7%) 788 (10.2 %) 0.95 (0.86-1.05)

Authors’ Conclusions

• A daily regimen of omega 3 fatty acids did not have a significantly lower incidence of serious vascular events versus placebo in diabetic patients without evidence of cardiovascular disease• These findings do not support routine dietary

supplementation with omega 3 fatty acids to prevent vascular events

Study CritiqueStrengths LimitationsLarge number of patients Included patients with well controlled

diabetes Randomized, double-blinded, interventional trial

Dose of omega-3 fatty acid supplementation

Relatively long follow-up Did not control for diet intake or other supplements

Results consistent with previous studies 8-10 week run-in period excluded non-adherent patients

Recommendations for Clinical Practice

• There is no justification for recommending fish oil supplements to protect against cardiovascular events• Encouraging a healthy diet containing fish 1-2 times a week

is most important

Omega-3 fatty acids for the primary and secondary prevention of cardiovascular diseaseCochrane Systematic Review July 2018

• 79 randomized trials involving 112,059 people • Assessed effects of consuming additional O3FAs, compared to usual

or lower O3FAs, on diseases of the heart and circulation• Results• Little or no effect on all-cause mortality, CV mortality, CV events, CHD

mortality, stroke, or arrhythmias• Possible reduction in CHD events (not maintained in sensitivity analyses)• Did not alter serious adverse events, adiposity, or lipids• Slightly reduced triglycerides and increased HDL

Cochrane Database of Systematic Reviews 2018, Issue 7.

Cochrane Review Authors’ Conclusions

• Moderate and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health• Previous suggestions of benefits from EPA and DHA supplements

appear to originate from trials with higher risk of bias• Long-chain omega 3 fatty acid supplements do not show protective

effects on the heart

Cochrane Database of Systematic Reviews 2018, Issue 7.

Acknowledgements

• Mary H. Parker, PharmD, FASHP, FCCP, BCPS-AQ Cardiology• Durham VA HealthCare System

• John Bucheit, PharmD, BCACP, CDE• VCU School of Pharmacy

• Zachary R. Noel, PharmD, BCPS• University of Maryland School of Pharmacy

• Tracy Macaulay, PharmD, AACC, BCPS-AQ Cardiology• University of Kentucky HealthCare

Questions?

Presenter: Nathan Wayne

Dr. Wayne is a PGY2 Cardiology Pharmacy Resident at University of Kentucky Healthcare. He graduated from the University of Georgia College of Pharmacy and completed his PGY1 Pharmacy Residency at UNC REX Healthcare in Raleigh, NC. His current practice interests include critical care cardiology and cardiothoracic surgery. After residency, Dr. Wayne plans to obtain a position as an inpatient cardiology pharmacist.

Use of aspirin to reduce risk of initial vascular events inpatients at moderate risk of cardiovascular disease (ARRIVE):

a randomized, double-blind, placebo-controlled trial

Nathan Wayne, PharmDUniversity of Kentucky Healthcare

ACCP PRN Cardiology Journal Club – October 2018

Mentor: Mary H. Parker, PharmD, BCPS-AQ Cardiology, FASHP, FCCP

Disclosures

• The speaker has no relevant financial relationships with commercial interests pertaining to the content of this presentation

Background

• Low-dose aspirin has an established role in secondary prevention of cardiovascular and cerebrovascular events due to its inhibition of platelet activation• Low-dose aspirin for primary prevention remains controversial• Many cardiovascular guidelines place emphasis on risk assessment

when choosing medications • ACC/AHA ASCVD Risk Calculator• The Prospective Cardiovascular Muenster Heart Study (PROCAM)• Framingham Cardiovascular Disease 10-year Risk • Systemic Coronary Risk Evaluation (SCORE)

BackgroundGuideline Population Recommendation Grade of

Recommendation

US Preventative Task Force (2016)

Adults age 50-59 years10-year CVD risk ≥ 10% Low-dose aspirin B

Adults age 60-6910-year CVD risk ≥ 10% Low-dose aspirin C

Adults less than 50 years, adults 70 years or greater

Insufficient evidence to support low-dose aspirin I

European Society of Cardiology (2016)

Patients without cardiovascular disease

Antiplatelet therapy is not recommended due to the

increased risk of major bleeding

III, B

Canadian Cardiovascular Society (2011)

Adults without evidence of manifest vascular disease

Aspirin at any dose is not recommended to prevent ischemic vascular events

III, A

Background

• Early studies (1980-1990s)• Antithrombotic Trialists’ Collaboration • Meta-analysis – Primary Prevention (~95,000 participants)• Decreases in non-fatal MI, any major coronary event, any serious vascular

event

• ASCEND – Patient with diabetes• ACCEPT-D – Patients with diabetes treated with statins• ASPREE – Patients of advanced age• ARRIVE – Patients with moderate cardiovascular risk

Trials 2007;8:21N Engl J Med 2018; 379:1529-1539

Contemp Clin Trials 2013;36:555-64Lancet 392.10152 (2018): 1036-1046

ARRIVE

• Objective • To investigate the efficacy of daily aspirin compared to placebo in people at

moderate risk for the reduction of incident myocardial infarction, stroke, and related cardiovascular conditions

• Design• Randomized, double-blind, placebo-controlled, multicenter study• Germany, Italy, Ireland, Poland, Spain, the UK, and the USA• Primary care offices

ARRIVE – Patient SelectionInclusion Criteria

• Female - 60 years or older with three or more risk factors • Male - 55 years or older, with two

to four risk factors• Risk Factors

• Female: total cholesterol > 240 mg/dL,LDL > 160 mg/dL; Male: total cholesterol > 200 mg/dL, LDL > 130 mg/dL

• HDL < 40 mg/dL• Current smoking • SBP > 140 mmHg• Receiving medication to treat high blood

pressure • Positive family history of cardiovascular

heart disease

Exclusion Criteria• History of a vascular event• Stroke, myocardial infarction,

coronary artery angioplasty or stenting, coronary artery bypass graft

• Relevant arrhythmias• Congestive heart failure• Vascular intervention• Required antiplatelet therapy• High risk of gastrointestinal and

other bleeding• Diabetes

ARRIVE – Outcomes

• Primary endpoint• Time to first occurrence of confirmed myocardial infarction, stroke,

cardiovascular death, unstable angina, or transient ischemic attack• Secondary endpoints• Time to first occurrence of cardiovascular death, myocardial infarction, or

stroke• Time to individual components of this composite secondary outcome• Time to first occurrence of unstable angina • Time to first occurrence of transient ischemic attack• Time to and incidence of all-cause mortality

• Safety/adverse events

ARRIVE – Statistical Analysis

• Primary and secondary endpoints• Intention-to-treat and per-protocol analyses• Two-sided log-rank test• Two-sided p value of 0.05 or less

• Safety analyses• Intention-to-treat population

• Event-driven design vs. time-driven design• Follow-up: 5 years

12,546 RandomizedJuly 5, 2007, and Nov 15, 2016

Aspirin 100 mg once daily6270 total

6245 received aspirin25 did not receive aspirin

6270 intention-to-treat analysis3790 per-protocol analysis*

Placebo once daily6276 total

6259 received aspirin17 did not receive aspirin

6276 intention-to-treat analysis3912 per-protocol analysis*

ARRIVE – Baseline Characteristics Characteristic Aspirin (n=6270) Placebo (n=6276)

Mean age, years 63.9 63.9Female sex 1851 (29.5%) 1857 (29.6%)Race, white 6133 (97.8%) 6146 (97.9%)Current cigarette smoker 1808 (28.8%) 1786 (28.5%)High total cholesterol 3647 (58.2%) 3657 (58.3%)High LDL 2775 (44.3%) 2869 (45.7%)Low HDL 857 (13.7%) 875 (13.9%)High Systolic Blood Pressure

Median SBP, mmHg3916 (62.5%)

1453950 (62.9%)

145Taking anti-hypertensive medications 4038 (64.4%) 4097 (65.3%)Country (USA) 247 (3.9%) 267 (4.3%)Mean Framingham risk score 13.9% 14.1%Mean ACC/AHA ASCVD risk score 17.3% 17.4%

ARRIVE – Primary Endpoint

• Intention-to-treat

• Per-protocol

Aspirin (n=6270)

Placebo (n=6276) HR (95% CI) p value

MI, stroke, CV death,

unstable angina, or TIA 269 (4.29%) 281 (4.48%) 0.96 (0.81-1.13) p=0.6038

Aspirin (n=3790)

Placebo (n=3912) HR (95% CI) p value

MI, stroke, CV death,

unstable angina, or TIA 129 (3.40%) 164 (4.19%) 0.81 (0.64-1.02) p=0.0756

MI: myocardial infarction, CV: cardiovascular, TIA: transient ischemic attack

ARRIVE – Secondary EndpointsIntention-to-treat Per-protocol

Aspirin (n=6270)

Placebo (n=6276)

HR (95% CI); p valueAspirin

(n=3790)Placebo

(n=3912)HR (95% CI); p value

MI, stroke, or CV death 208 (3.32%) 218 (3.47%)

0.95 (0.79-1.15);p=0.6190

103 (2.72%) 135 (3.45%)0.79 (0.61-1.02);

p=0.0661

MI95 (1.52%) 112 (1.78%)

0.85 (0.64-1.11);p=0.2325

37 (0.98%) 72 (1.84%) 0.53 (0.36-0.79);p=0.0014

Non-fatal MI88 (1.40%) 98 (1.56%)

0.90 (0.67-1.20);p=0.4562

32 (0.84%) 60 (1.53%)0.55 (0.36-0.84);

p=0.0056

Stroke75 (1.20%) 67 (1.07%)

1.12 (0.80-1.55);p=0.5072

40 (1.06%) 37 (0.95%)1.12 (0.71-1.75);

p=0.6291

CV death38 (0.61%) 39 (0.62%)

0.97 (0.62-1.52);p=0.9010

26 (0.69%) 26 (0.66%)1.03 (0.60-1.77);

p=0.9161

Any death160 (2.55%) 161 (2.57%)

0.99 (0.80-1.24);p=0.9459

108 (2.85%) 101 (2.58%)1.10 (0.84-1.45);

p=0.4796

Unstable angina 20 (0.32%) 20 (0.32%)

1.00 (0.54-1.86);p=0.9979

8 (0.21%) 11 (0.28%)0.75 (0.30-1.87);

p=0.5380

TIA42 (0.67%) 45 (0.72%)

0.93 (0.61-1.42);p=0.7455

19 (0.50%) 19 (0.49%)1.10 (0.84-1.45);

p=0.4796MI: myocardial infarction, CV: cardiovascular, TIA: transient ischemic attack

ARRIVE – Safety and Adverse Events Aspirin (n=6270) Placebo (n=6276) HR (95% CI); p value

Total serious adverse events 1266 (20.19%) 1311 (20.89%) -

Any gastrointestinal bleedSevereModerateMild

61 (0.97%)4 (0.06%)

12 (0.24%)42 (0.67%)

29 (0.46%)2 (0.03%)5 (0.08%)

22 (0.18%)

2.11 (1.36-3.28); p=0.0007---

Hemorrhagic stroke 8 (0.13%) 11 (0.18%) -

Osteoarthritis 104 (1.66%) 103 (1.64%) -

Any treatment-relatedadverse events

DyspepsiaEpistaxisGERDUpper abdominal pain

1050 (16.75%)

226 (3.60%)116 (1.85%)70 (1.12%)68 (1.08%)

850 (13.54%)

197 (3.14%)56 (0.89%)60 (0.96%)58 (0.92%)

p<0.0001

----

GERD: gastroesophageal reflux disease

ARRIVE – Discussion and Conclusions

• Aspirin treatment did not lower risk of major cardiovascular events, but did increase risk of gastrointestinal bleeding

• Current practice consists of multiple preventative and therapeutic interventions leading to lower than expected cardiovascular risk• Estimated ASCVD 17.3% vs. Actual rate of ASCVD events <10%

• Clinicians and patients should evaluate the risks and benefits of aspirin therapy for primary prevention on an individual basis

Study Critique

Limitations• High number of participants

who prematurely terminated the study • Lower than expected event rates• Self-reported compliance• Participants reflect a low-risk

instead of a moderate-risk population

Strengths• Large, randomized, double-

blind, placebo-controlled, multicenter study• Attempted a pragmatic, primary

care-based randomized trial

ASCEND – Aspirin

• n= 15,480, aspirin 100 mg daily vs placebo • Primary Efficacy Outcome: Any serious vascular event (nonfatal MI,

nonfatal stroke, TIA, death from any vascular cause)• Aspirin=658 (8.5%) vs. Placebo=743 (9.6%); HR 0.88 (95% CI 0.79-0.97); p = 0.01

• Primary Safety Outcome: Any major bleeding (intracranial hemorrhage, sight-threatening bleeding of the eye, gastrointestinal bleeding, any other bleeding requiring hospitalization, transfusion, or death)• Aspirin=314 (4.1%) vs. Placebo=245 (3.2%); HR 1.29 (95% CI 1.09-1.52); p = 0.003

• Aspirin may have benefit in reducing vascular events in patients with well-controlled diabetes, but use also increases major bleeding

Conclusions and Application

• Clinicians and patients should evaluate risks and benefits on an individual basis when considering aspirin therapy for primary prevention

• Current risk calculation methods may overestimate 10-year risk of cardiovascular disease• Evaluation of risk calculation methods is warranted in order to reflect more

contemporary estimates of cardiovascular risk

Acknowledgements

• Mary Parker, PharmD, BCPS (AQ Cardiology), FASHP, FCCP• Zachary Noel, PharmD, BCPS• John Bucheit, PharmD, BCACP, CDE• Tracy Macaulay, PharmD, AACC, BCPS (AQ Cardiology)

Use of aspirin to reduce risk of initial vascular events inpatients at moderate risk of cardiovascular disease (ARRIVE):

a randomized, double-blind, placebo-controlled trial

Nathan Wayne, PharmDUniversity of Kentucky Healthcare

ACCP PRN Cardiology Journal Club – October 2018

Mentor: Mary H. Parker, PharmD, BCPS-AQ Cardiology, FASHP, FCCP