Virginia ACP MSFM Session- Lipid Management & CVD Risk Reduction -

Q1. What is the evidence that adding a second pharmacologic agent to statin therapy improves cardiovascular outcomes?

1a. Fibrates for high triglyceride

1b. Niacin for low HDL

Relationship Between LDL-C Levels and CHD Events

40 70 100 130 160 190 220

LDL-Cholesterol (mg/dl)

Relative Riskof CHD

(log scale)

3.7

2.9

2.2

1.7

1.3

1.0

0

“Rule of One” applies when

LDL < 100 mg/dl•

•

••

•

•

Data derived from epidemiologic studies and RCTs

Circulation 2004;110:227-39

Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis

Lancet 2010; 375: 1875-84

• 18 RCTs published between 1971-2010• Data for 45,058 patients, including 4552 major CHD events

and 3880 deaths• Clofibrate (7 RCTs), Bezafibrate (4 RCTs), Gemfibrozil

(3RCTs), Fenofibrate (3 RCTs) and Etofibrate (1 RCT)

… The ACCORD-LIPID study is the first (and only) large-scale RCT (as of March 2013) to evaluate the impact of a fibrate/statin combination versus statin monotherapy on major cardiovascular outcomes.

N Engl J Med 2010; 362: 1563 - 74

J. Am Coll Cardiol 2013; 61: 440-46

• 11 RCTs published between 1975-2011• Data for 9959 patients, 1547 CHD deaths and non-fatal

MIs • Niacin (IR, ER) 0.25- 7.5 gm/day

Effect of Niacin Therapy on Major CHD Events

J Am Coll Cardiol 2013;61:440-446

…The AIM-HIGH study is the first (and only) large-scale RCT (as of March 2013) to evaluate the impact of a niacin/statin combination versus statin monotherapy on major cardiovascular outcomes.

N Engl J Med 2011; 365: 2255 - 67

Why Have Trials Failed When a Second Agent is Added to a Statin?

ACCORD-LIPID• End-of-study LDL-C 80 mg/dl for statin/placebo vs 81

mg/dl for statin/fenofibrate

AIM-HIGH• End-of-study LDL-C 68 mg/dl for statin/placebo vs

65 mg/dl for statin/niacin ER

European Heart J 2011; 32:1769 -1818

Recommendations for the Pharmacological Treatment of Hypercholesterolemia

European Heart Journal (2011) 32, 1769-1818

Virginia ACP MSFM Session- Stroke Prevention in AF/AFL -

Q2. Given the emergence of several new oral anticoagulants (NOACs), what is the best method to prevent stroke in patients with non-valvular atrial fibrillation or flutter?

2a. Who should receive OAC therapy?

2b. Which OAC is preferred?

Novel Oral Anticoagulants- FDA approved NOACs -

Direct Thrombin Inhibitors

- Dibigatran (Pradaxa) October 2010

Factor Xa Inhibitors

- Rivaroxaban (Xarelto) November 2011

- Apixaban (Eliquis) December 2012

Stroke Prevention Guidelines- 2012 Updates Triggered by NOACs -

• Canadian Cardiovascular Society• American College of Chest Physicians• European Society of Cardiology• American Heart/Stroke Association

2012 Updated AF Guidelines- What are the common themes? -

1. Physicians tend to underestimate the benefits of OAC and overestimate risk of bleeding, especially in elderly

2. Most algorithms place greater weight on the deaths/strokes prevented by OAC and less weight on the major bleeds that are caused

3. Many patients with a CHADS2 score of 1 (and even some with a score of 0) should be offered OAC therapy

2012 Updated AF Guidelines- What are the Common Themes? -

4. Use of CHA2DS2-VASc scoring index helps stratify “low” and “intermediate” risk patients (CHADS2 = 0-1)

5. ASA and ASA/Clopidogrel therapy is inferior to OAC (patients should be informed).

6. AF Strokes are devastating and the #1 preventable cause of stroke.

Advantages of OAC

- Strong Evidence from Warfarin RCTs -

• Reduce all-cause mortality (~ 28%)• Reduce risk of stroke (~ 68%)• Reduce non-CNS systemic embolism (20-

75%)• Net clinical benefit

Atrial fibrillation, anticoagulation, fall risk, and outcomes in elderly patients

Matthew B. Sellers, MD, and L. Kristin Newby, MD, MHSDuke University Health System, Durham, North Carolina

American Heart Journal 2011; 161: 241-6

…if the annual stroke rate is ≥ 2%, quality-adjusted life expectancy is greatest for OAC, followed by APT and no therapy, respectively.

…analysis show that an elderly patient would have to fall ~ 300 times per year for the risk of bleeding complications from falling to outweigh the benefits for prevention of embolic stroke.

Gage, BF, et. al., JAMA 2001; 285: 2864-2870

Annual Risk of Stroke & OAC Threshold- Original validation cohort study, comprising 1733 pts -

Safety and Efficacy of OAC versus DAPT - Outcome analysis by CHADS2 score -

Healey, JS. Stroke 2008; 39: 1482-86

Recommendations for Antithrombotic Use - Summary of 2012 ESC, ACCP and CCS AF Guidelines -

1 European Heart Journal, 2010; 31: 2369-24292 Chest, 2012; 141(2); e531-5753 Canadian Journal of Cardiology, 2012; 28(2): 125-136

CHA2DS2-VASc and CHADS2 Scores

*CAD/prior MI, PAD or aortic plaque

The value of the CHA2DS2-VASc Score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: A nationwide cohort study

Olesen JB, Torp-Pedersen C, Hansen ML and Lip GY

Department of Cardiology, Copenhagen University Hospital and University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK

Thrombosis and Haemostasis 2012; 107: 1172-79

Olesen, JB. Thrombosis and Haemostasis 2012; 107: 1172-79

Olesen, JB. Thrombosis and Haemostasis 2012; 107: 1172-79

Canadian Journal of Cardiology, 2012; 28(2): 125-136

Antithrombotic Management of AF/AFL in CAD

* within past year

Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a ‘real world’ atrial fibrillation population: A modelling analysis based on a nationwide cohort study

Amitava Banerjee, Dierdre A. Lane, Christian Torp-Pedersen, Gregory Y.H. LipUniversity of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK; Department of Cardiolgy, Copenhagen University Hospital Gentofte, Denmark

Thrombosis and Haemostasis 2012; 107: 584-89

Beneficial Effects of NOACs Compared to Warfarin- The “Big 3” RCT’s, comprising 50,576 AF Patients -

Questions?

2011; Volume 123: 2292-2333

Triglycerides and Cardiovascular Disease: A Scientific Statement from the American Heart Association

Michael Miller, Neil J. Stone, Christie Ballantyne, Vera Bittner, Michael H. Criqui, Henry N. Ginsberg, Anne Carol Goldberg, William James Howard, Marc S. Jacobson, Penny M.

Kris-Eterton, Terry A Lennie, Moshe Levi, Theodore Mazzone, Subramian Pennathur

Results of the ACCORD-LIPID Trial

Years

% P

ts w

/Eve

nts

Results of the AIM-HIGH Trial

N Engl J Med 2011; 365:2255-67.

Optimal LDL-C Is 50 to 70 mg/dlLower Is Better and Physiologically Normal

James H. O’Keefe, Jr., Loren Cordain, William H. Harris, Richard M. Moe, and Robert Vogel

EXPEDITED REVIEW

J Am Coll Cardiol 2004;43:2142-6

Connolly, SJ, et. al., New England Journal of Medicine 2011; 364: 806–817

Results of the AVERROES Trial- 5559 pts with AF and CHADS2 Score ≥ 1.0, unsuitable for warfarin therapy -

Stroke or Systemic Embolism

Major Bleeding

Months Months

RRR= 55%

AF and Cardio-embolic Stroke- AF is #1 preventable cause of stroke -

• Large clot burden – devastating sequalae• Higher mortality (10-25% case fatality)• Greater disability (40% bedriden)• Less responsive to IV thrombolysis• Higher recurrence rate• ICH reduced by 40-75% with NOCAs

Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a ‘real world’ nationwide cohort study

Jonas Bjerring Olesen, Gregory Y.H. Lip, jesper Lindhardsen, Deirdre A. Lane, Ole Ahlehoff, Morten Lock Hansen, Jakob Raunso, Janne Schurmann Tolstrup, Peter Riis Hansen, Gunnar Hilmar Gislason, Christian Torp-PedersenUniversity of Birmingham Centre for Cardiovascular Sciences, and National Institute of Public Health, Copenhagen, Denmark

Thrombosis and Haemostasis 2011; 106: 739-49

HAS-BLED Bleeding Risk Score

Low Risk = 0-1Moderate Risk = 2High Risk ≥ 3

Management of Bleeding in Patients Taking NOAL

PCC = prothrombin complex concentraterF7a = activated recombinant factor VII* With dabigatran

Results of the ARISTOTLE Trial- 18,201 patients with AF and CHADS2 score ≥ 1.0 -

Granger, CB, et. al., New England Journal of Medicine 2011; 365: 981-992

Stroke or Systemic Embolism Major Bleeding

Months Months

RRR=21%, p<.01 RRR=31%, p<.001

ARISTOLE: Intracranial Bleeding