New Paradigms in the Science and Medicine of Heart Disease

New Frontiers

in

Stroke Prevention

for

Atrial Fibrillation

Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic Interventions for Stroke Prevention in Atrial Fibrillation (SPAF) Program Chairman Allan V. Abbott, MD Program Chair and Moderator Professor of Clinical Family Medicine Associate Dean of Continuing Medical Education Keck School of Medicine University of Southern California

Program Faculty

Allan V. Abbott, MD

Program Chair and Moderator Professor of Clinical Family Medicine Associate Dean of Continuing Medical Education Keck School of Medicine University of Southern California Los Angeles, California

Scott Kaatz, DO, MSc, FACP

Clinical Associate Professor of Medicine Associate Residency Program Director Department of Medicine Director, Anticoagulation Clinics Henry Ford Hospital Detroit, Michigan

Alan K. Jacobson, MD, FACC

Assistant Professor Loma Linda University School of Medicine Director, Anticoagulation Services Associate Chief of Staff for Research Loma Linda Veterans Affairs Medical Center Loma Linda, California

Annabelle S. Volgman, MD, FACC

Associate Professor of Medicine Medical Director Heart Center for Women Rush University Medical College Chicago, Illinois

New Paradigms in the Science and Medicine of Heart Disease

New Frontiers

in

Stroke Prevention

for

Atrial Fibrillation

Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic Interventions for Stroke Prevention in Atrial Fibrillation (SPAF) Program Chairman Allan V. Abbott, MD Program Chair and Moderator Professor of Clinical Family Medicine Associate Dean of Continuing Medical Education Keck School of Medicine University of Southern California

A Brief History

► 1628, William Harvey was probably the first to describe "fibrillation of the auricles" in animals.

► 1785 William Withering recorded digitalis leaf brought some relief to patients with severe heart failure.

► 1900, Sir Thomas Lewis in London was the first to record an electrocardiogram in a patient with atrial fibrillation.

► However the exact mechanisms and importance remained controversial until the 1970s.

Epidemiology of Atrial Fibrillation

► ► ► ► Atrial fibrillation is fairly uncommon in people under 50 years but is found in 0.5% of people aged 50-59, increasing to 8-8% at age 80-89.

Atrial fibrillation may be either chronic or paroxysmal. In the Framingham study, hypertension, cardiac failure, and rheumatic heart disease were the commonest precursors of atrial fibrillation.

About a third of patients have idiopathic or "lone" atrial fibrillation - no precipitating cause can be identified and no evidence of structural heart disease exists.

Treatment, A Brief History

► 1982, The epidemiological importance of atrial fibrillation as an important precursor of cardiac and cerebrovascular death was investigated by William Kannell and colleagues.

► 1980s-1990s, awareness increased of the hazards of sustained atrial fibrillation and the benefits of prophylaxis against thrombosis in preventing stroke.

► Early treatment was electrical or chemical cardioversion, digitalis for rate control, and warfarin or aspirin for prevention of thromboemboli.

Treatment, Last Decade

► Rate control with beta-blockers and/or calcium channel blockers (digoxin or amiodarone if CHF) ► Cardioversion, heparin and electrical or chemical cardioversion then warfarin ► Warfarin with its associated risk of bleeding and requirement for frequent monitoring remains standard today

Treatment, Evolving Paradigms New treatments

►

End the atrial fibrillation with catheter ablation or surgical approaches

►

Replace warfarin with novel oral anticoagulants ablate

Treatment, Evolving Paradigms Ablation Procedures

Treatment, Evolving Paradigms

Novel oral anticoagulants

New Paradigms in the Science and Medicine of Heart Disease

Epidemiology, Risk Stratification, and Individualized Therapy in Atrial Fibrillation

Aligning Stroke-Preventing Strategies with Appropriate Patient Subgroups Annabelle S. Volgman, MD FACC Associate Professor of Medicine Medical Director, Heart Center for Women Rush University Medical Center Chicago, IL

Outline

►

Epidemiology, risk stratification, and individualized therapy in atrial fibrillation ● Aligning stroke-preventing strategies with appropriate patient subgroup

►

The Role of Risk Stratification for Identifying Antithrombotic Strategies for Stroke Prevention: ● Evidence-based options for the family medicine specialist at the front lines of care

ATRIA: Prevalence of atrial fibrillation increases with age 12 10 8 Prevalence (%) 6 4 2 0 <55 55-59 Women (n = 7801) 60-64 65-69 70-74 Age (years) Men (n = 10,173) 75-79 80-84 ≥85

Go AS et al.

JAMA

. 2001;285:2370-5.

Prevalence of AF in Adults Aged 65-84 Years (% of Total Population), 1968-1989 Adults 1968 1970 1971 1973 1975 1977 1979 1981 1983 1985 1987 1989 Men Women 3.2

2.8

5.3

3.3

6.5

4.3

7.8

4.3

7.5

3.9

9.1

4.7

Pilote, L. et al. CMAJ 2007;176:S1-S44

Atrial Fibrillation: Framingham Study

Age 50-59 60-69 70-79 80-89 Wolf PA et al. Stroke. 1991;22-983-8.

AF Prevalence (%) Strokes Attributable to AF (%) 0.5

1.8

4.8

8.8

6.5

8.5

18.8

30.7

Lifetime Risk of Developing AF

►

40 years old ● Men ● Women ● ● 26% 23%

►

80 years old ● Men ● Women ● ● 23% 22% The lifetime risk for AF was approximately 16% in the absence of a history of congestive heart failure or myocardial infarction. Lloyd-Jones DM et al. Circulation 2004.

Factor Obesity/MS/DM Alcohol Statins ACE-I/ARBs Fish/Fish oils Vitamin E

Factors that Affect Developing Primary Atrial Fibrillation

Study VALUE 1 WHS 2 Multiple 3 Multiple 4 Multiple 5 WHS 6 Effect Increase Increase Decrease Decrease Decrease (post-op) No effect 1 Aksnes TA et al. Am J Cardiol. 2008 Mar 1;101(5):634-8 3 Faucier L et al. J Am Coll Cardiol, 2008; 51:828-835, 4 2 Conen, D et al. JAMA Dec 2008, 300 (21):2489-96.

Healey et al. J Am Coll Card, 2005: 45:1832-1839, 5 Cheng W et al. J Altern Complement Med. 2008 Oct;14(8):965-74. 6 Ganz LI et al. Heart Rhythm 2008.

Stroke Risk Increases with Age

Gender Differences in the Risk of Ischemic Stroke and Peripheral Embolism in AFib The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) Study Fang,MC et al. Circulation.

2005;112:1687-1691

Copenhagen City Heart Study

►

The independent effect of AF on stroke rate was 4.6-fold greater in women than in men: ● Hazard ratio in women 7.8 (95% CI, 5.8 to 14.3) ● Hazard ratio in men 1.7 (95% CI, 1.0 to 3.0)

►

The independent effect of AF on the cardiovascular mortality rate was 2.5-fold greater in women than in men: ● Hazard ratio in women 4.4 (95% CI, 2.9 to 6.5) ● Hazard ratio in men 2.2 (95% CI, 1.6 to 3.1) Friberg J et al. American Journal of Cardiology 2004; 94: 889-894

Patients Older than 75 Years Less likely to Receive Therapy for CV Events

►

Patients older than 75 years of age ● <50% chance of receiving clinically proven treatments for cardiovascular events such as MI and atrial fibrillation as compared to younger patients.

►

Conclusion: elderly.

The study results suggest that physicians need to be more aware of and willing to use indicated treatments in the Ganz DA et al.Journal of the American Geriatric Society 1999; 47: 145-150

Risk Factors of Ischemic Stroke & Systemic Embolism in Patients with Nolvalvular Atrial Fibrillation Risk Factors Previous stroke or TIA Diabetes mellitus History of hypertension Heart failure Advanced age (continuous, per decade) Relative Risk 2.5

1.7

1.6

1.4

1.4

AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

Stroke Risk with Nolvalvular AF Not Treated with Anticoagulation According to the CHADS2 Index CHADS 2 Risk Criteria Previous stroke or TIA Age > 75 years Hypertension Diabetes mellitus Heart failure Score 1 1 2 1 1 Patients (N = 1733) 120 463 523 337 220 65 5 Adjusted Stroke Rate (%/y) 1.9 (1.2 to 3.0) 2.8 (2.0 to 3.8) 4.0 (3.1 to 5.1) 5.9 (4.6 to 7.3) 8.5 (6.3 to 11.1) 12.5 (8.2 to 17.5) 18.2 (10.5 to 27.4) (95% CI) AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

CHADS 2 0 Score 1 2 3 4 5 6

Risk Stratification Schemes Use to Predict Thromboembolism with Nonvalvular AF Fang MC et al. JACC 2008, 51(6):810-15.

Annual TE Rates Across Risk Groups Using 5 Risk Stratification Schemes Used to Predict AF-Related TE Fang MC et al. JACC 2008, 51(6):810-15.

New Frontiers for Stroke

Prevention in Atrial Fibrillation

Annabelle S. Volgman, MD FACC Associate Professor of Medicine Medical Director, Heart Center for Women Rush University Medical Center Chicago, IL

Meta-analysis of Stroke Prevention for High Risk Atrial Fibrillation Trials

►

Adjusted dose warfarin ● ● Stroke Risk Reduction – 60% Death Risk Reduction – 25%

►

Antiplatelet therapy ● Stroke Risk Reduction – 20%

►

Advantage of warfarin over antiplatelet therapy ● Stroke Risk Reduction– 40% Hart R, Pearce L, Aguilar M. Annals of Internal Medicine.

June 2007,146:857-67.

Analysis of 5 Antithrombotic Trials

►

Women > 75 years were 54% less likely to receive warfarin and twice as likely to receive aspirin

►

Warfarin reduced stroke risk by 84% in women and 60% in men

►

ASA resulted in significantly decreased stroke risk in men (44%) but not in women (23%) Pilote L, CMAJ.

2007; 176(6):S1-44.

Physician and Patient Reluctance

►

CARAF* demonstrated that women on warfarin were 3.35 times more likely to experience major bleeding.

►

Nine of ten women who experienced major bleeds were < 75 years old.

►

INRs at time of bleeding were elevated, but the levels were similar in men and women.

* Canadian Registry of Atrial Fibrillation Humphries KH et al. Circulation. 2001; 103:2365-70

AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

Bleeding Risks

►

SPORTIF Trial

►

Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study

► ►

Women > Men (p=0.001 minor; p=NS major/minor) 1.0% for women versus 1.1% for men

►

Stroke Prevention in Atrial Fibrillation (SPAF) studies

►

Annual bleeding rates were 1.5%, 1.7% and 2.1% both genders Gomberg-Maitland M, Wenger NK, Feyzi J, Lengyel M, Volgman AS, Petersen P, Frison L, Halperin JL. Eur Heart J. 2006; 27:1947-53. Fang MC, et al. Circulation. 2005; 112:1687-91. Lancet. 1996; 348:633-8.

Summary

►

Individualize anticoagulation therapy for patients with atrial fibrillation

►

Low risk patients should be treated with aspirin

►

Intermediate to high risk patients benefit from anticoagulation but bleeding risks may offset benefit

►

If bleeding risk is

minimized

from anticoagulation , intermediate risk patients would have improved risk/benefit ratio

New Paradigms in the Science and Medicine of Heart Disease

The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease

Mechanisms and Recent Clinical Trials

Scott Kaatz, DO, MSc, FACP

Clinical Associate Professor of Medicine Associate Residency Program Director Department of Medicine Director, Anticoagulation Clinics Henry Ford Hospital Detroit, Michigan

The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease Mechanisms and Recent Clinical Trials

►

Anticoagulant options in atrial fibrillation

►

Warfarin

►

Dabigatran

►

Apixaban

►

Rivaroxaban

Stroke Rate per Year with Different Antithrombotic Options in AF

Option No treatment ASA ASA + Clopidogrel Warfarin Apixaban Dabigatran 110 Dabigatran 150 Approximate Rate/Year 4.5% 3.5% 2.5% 1.5% 1.5% 1.5% 1.0% Hart 4.5% 3.2% 1.8% ACTIVE W ACTIVE A AVERROES RELY Thrombin Yes 2.4% 1.4% Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005 Connolly S. Lancet. 2006 Jun 10;367(9526):1903-12. PMID: 16765759 Connolly SJ. N Engl J Med. 2009 May 14;360(20):2066-78. PMID: 19336502 Connolly S. Hotline session at ESC 8.31.10

Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844 3.3% 2.4% 3.3% 1.5% 1.6% 1.4% 1.0%

Comparative Pharmacology

Characteristic Target Prodrug Bioavailability Dosing Half life Renal clearance Routine coag. monitoring Drug interactions Apixaban Rivaroxaban Factor Xa No 60% Fixed, b.i.d.

12 hours 25% No Factor Xa No 80% Fixed, o.d.

7 to 11 hours 35% No Potent CYP3A4 & P-gp inhibitors Potent CYP3A4 & P-gp inhibitors Dabigatran Thrombin Yes 6% Fixed, o.d./bid 12-17 hours 80% No Potent P-gp inhibitors Courtesy of John Eikelboom

The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease Mechanisms and Recent Clinical Trials

►

Anticoagulant options in AF

► Warfarin ►

Dabigatran

►

Apixaban

►

Rivaroxaban

Warfarin

http://www.anaesthesia

uk.com/images/clotting _cascade.gif

Warfarin

• Warfarin was launched as the ideal rat poison in 1948. Although it was thought at first to be too toxic for human use

► ►

In 1951 the failed attempted suicide of a navy recruit who had taken a large dose of rat poison led clinicians to discard dicumarol in favor of warfarin.

The first clinical study with warfarin was reported in 1955. In the same year, President Eisenhower was treated with warfarin following a heart attack Scully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdf

Warfarin vs. no Treatment or Placebo

Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005

The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease Mechanisms and Recent Clinical Trials

►

Anticoagulant options in AF

►

Warfarin

► Dabigatran ►

Apixaban

►

Rivaroxaban

Direct Thrombin Inhibitors

http://www.anaesthesia

uk.com/images/clotting _cascade.gif

Medicinal Leech (Hirudo Medicinalis)

•Scientific interest in leeches date back to ancient India •However, the first Western citation is credited to the Greek, Nicander of Colophon (130 BC) •This therapeutic use of leeches, the medicinal leech in particular, reached a height between 1825 and 1840. •A more contemporary use of leeches was discovered in 1957 by Markwardt •The leech secretion hirudin was isolated and subsequently its anticoagulant properties with respect to the elucidation of blood clotting mechanisms were examined.

http://soma.npa.uiuc.edu/courses/physl490b/models/leech_swimming/leech_swim.html

RELY Trial

► ► ► ► ► ► ►

Question: Is Dabigatran oral unmonitored direct thrombin inhibitor as effective and safe as warfarin for stroke prevention in AF?

Design: Randomized trial, warfarin was un-blinded Patients: 18,113 AF patients with at least on stroke risk factor Interventions: ● ● Dabigatran 110 mg bid Dabigatran 150 mg bid Comparison: Warfarin, INR 2.0-3.0

Primary outcome: Stoke and systemic embolism Timeframe: Mean follow up was 2.0 years Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

RELY

Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

RELY

Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

RELY

Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease Mechanisms and Recent Clinical Trials

►

Anticoagulant options in AF

►

Warfarin

►

Dabigatran

► Apixaban ►

Rivaroxaban

AVERROES

►

Question: Is apixaban superior to ASA in patients with AF who are not candidates for warfarin?

►

Design: RCT, double blinded

►

Patients: AF patients not candidates for warfarin

►

Intervention: apixaban 5 mg (2.5 mg) bid

►

Comparison: ASA 81-325 mg qd

►

Outcome: stroke or systemic embolism Connolly S. Hotline, ESC, 8.31.10

Connolly S. Hotline, ESC, 8.31.10

Connolly S. Hotline, ESC, 8.31.10

Connolly S. Hotline, ESC, 8.31.10

The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease Mechanisms and Recent Clinical Trials

►

Anticoagulant options in AF

►

Warfarin

►

Dabigatran

►

Apixaban

► Rivaroxaban

ROCKET

► ► ► ► ► ►

Question: is rivaroxaban non-inferior to warfarin for stroke prevention in AF Design: RCT, double blinded Patients: AF and CHADS 2 > 2 Intervention: rivaroxaban 20 mg qd Comparison: warfarin Outcome: ● Stroke and systemic embolism ● Major and non-major clinically relevant bleeding

►

Result expected to be presented at AHA, November 2010 www.clinicaltrials.gov NCT00403767

The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease Mechanisms and Recent Clinical Trials

►

Anticoagulant options in AF

►

Warfarin

►

Dabigatran

►

Apixaban

►

Rivaroxaban

New Paradigms in the Science and Medicine of Heart Disease

Optimizing Stroke Prevention in AF with Established and Currently Available Therapies

The Role of Vitamin K Antagonists – What Works? What Doesn’t?

Alan K. Jacobson, MD Director, Anticoagulation Services Loma Linda VA Medical Center Loma Linda, California

Why do we need another warfarin management lecture?

►

Warfarin therapy is: ● ● Highly effective Complex to manage ● ● Underutilized When utilized, managed poorly … but effective solutions have evolved.

Blood Flow in Atrial Fibrillation

Disturbed Flow (left atrium) Stroke Risk

Warfarin in Prospective AF Trials Intention-to-treat analysis

8 Control Warfarin 7.0

6 4 4.6

2 1.9

person-years p value 0 AFASAK 825 p=0.03

3.0

2.3

0.4

SPAF 504 BAATAF 922 p=0.01 p=0.002

3.6

2.1

CAFA 490 p>0.2

4.3

0.9

SPINAF 896 p=0.001

Adapted from

Atwood, Albers, Herz 1993;18:27-38

Anticoagulant Therapy is Effective

RR 79% 83% Loma Linda VA Medical Center, 2010 83% 73% 79% 83%

X OR vs.

Anticoagulation of AF Risk — Benefit

Oral Anticoagulation - Challenges

►

Narrow therapeutic dosing range ● 10-15% dosing window

►

Variable dosage requirement ● ● ● Effect of medications Effect of diet Effect of liver function

►

Serious consequences if dosing wrong

Burdens of Anticoagulation

►

Restricted diets Vitamin K NOTHING green, NO

►

Restricted medications NSAIDS NO aspirin, NO

►

Ongoing need for blood tests to check PT/INR

►

Burdens affect patients and providers

►

Clinical practice has often been driven more by tradition than science

Burdens of Anticoagulation

►

Solutions: ● ● Diet CONSISTENT Drug interactions Vitamin K intake CONSISTENT if NECESSARY ● Minimal need for restrictions, in fact, some may benefit from supplementation ● Prothrombin time testing and management…. ??

Systematic Anticoagulation Management

Direct Active Management by Qualified Health Care Provider Ongoing Patient Education Ongoing QI Patient-specific Decision Support and Interaction Patient Scheduling and Tracking Accessible, Accurate, and Frequent PT/INR Testing

Enabling Technologies: POC testing, computerization

Quality Question Are you able to identify, on an ongoing basis, which patients are overdue for testing?

Active vs. Passive Management

Patients Assigned to Warfarin in AF Trials Intensity of Anticoagulation When Stroke Occurred 4.0

1.8

1.7

INR Ratio 3.0

2.0

1.0

1.6

1.5

1.4

1.3

1.2

1.1

1.0

PT Ratio (ISI 2.4) AFASAK CAFA SPAF I BAATAF SPINAF ACCP recommendations: INR 2.0

–3.0

Petersen et al. Lancet 1989:171 –75 SPAF. Circ 1991;84:527 –39 BAATAF. N Engl J Med 1990; 323:1505 –11

Target range for individual study

Connolly et al. J Am Coll Cardiol 1991;18:349 –55 Ezekowitz et al. N Engl J Med 1992;327:1406 –12 Hirsh, Dalen, Deykin, Poller. CHEST 1992;312S –326S

PERCEIVED

INR Therapeutic Range

Bleed Risk Clot Risk

1 2 7 3 4 INR Intensity 5 6

ACTUAL

INR therapeutic range 100 80 60 40 20 0 INR INR-Specific Incidence of All Adverse Events (All Episodes of Thromboembolism, All Major Bleeding Episodes, and Unclassified Stroke).

Cannegeiter et al The dotted lines indicate the 95 percent confidence interval.

Incidence Rates of Ischemic Stroke and Intracranial Hemorrhage

Adapted from Hylek EM, et al. N Engl J Med. 2003;349:1019-1026.

Recommended Range for Warfarin Therapy

For Patients in Atrial Fibrillation

►

Target: INR 2.5

►

Range: INR 2.0–3.0

CHEST 1998;114:579s-589s

Methods of Monitoring - Options

►

Central Laboratory Testing with Professional Management of Results

►

Point-of-Care Testing

(Professional)

Professional Management of Results with

►

Point-of-Care Testing

(Patient)

Professional Management with Patient or Which is best???

Different solutions for different patients in different settings

Why do we need another warfarin management lecture?

►

Warfarin therapy is: ● ● ● ● Highly effective Complex to manage Underutilized When utilized, managed poorly … but effective solutions have evolved.

Progress of Medicine

►

Out of the enormous number of medicinal agents brought under our notice by puffing advertisements in the press, medical as well as lay, by pamphlets or even large books delivered by post, or by actual 'specimens for trial' which are nowadays so liberally delivered at our residences, comparatively few hold their ground, or stand a fair and candid criticism and investigation of their vaunted merits. Still a certain proportion do and I see every reason to anticipate that, as the result of the systematic researches, scientific and practical, now carried on in so many laboratories, valuable additions will be made from time to time to the medicinal agents at our disposal for the help and comfort of our patients. I only hope that in our love for the new we will not entirely throw out old friends which have done real and effective service in the past and are today as deserving of our regard as ever (Lancet 1899, Dr. F. Roberts).

Progress of Medicine

►

Out of the enormous number of medicinal agents brought under our notice by puffing advertisements in the press, medical as well as lay, by pamphlets or even large books delivered by post, or by actual 'specimens for trial' which are nowadays so liberally delivered at our residences, comparatively few hold their ground, or stand a fair and candid criticism and investigation of their vaunted merits. Still a certain proportion do and I see every reason to anticipate that, as the result of the systematic researches, scientific and practical, now carried on in so many laboratories, valuable additions will be made from time to time to the medicinal agents at our disposal for the help and comfort of our patients.

►

I only hope that in our love for the new we will not entirely throw out old friends which have done real and effective service in the past and are today as deserving of our regard as ever.

The Future

►

Refined management of the old drug – warfarin

►

Variety of new agents with predictable therapeutic ranges and improved risk benefit but with continued need for education, hemorrhagic risk assessment, and monitoring

►

Improved range of options to facilitate stroke prevention in patients with atrial fibrillation