Do Antiplatelet Medications Have the Same Efficacy

Running head: DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Do Antiplatelet Medications Have the Same Efficacy as Anticoagulants for Preventing

Thromboembolic Events in Atrial Fibrillation patients?

Deborah Andrews

University of Central Florida DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

ABSTRACT 2 Objective To evaluate antiplatelet agents in comparison to anticoagulant agents for thromboembolic stroke prevention in atrial fibrillation patients.

Background Thromboembolic stroke results most frequently from atrial fibrillation. Anticoagulant agents and aspirin are used for stroke prevention. Warfarin treatment is difficult and can cause serious complications. New antiplatelet agents beginning to be utilized.

Methods Data bases were searched to extract articles for literature review in: CINAHL Plus, MEDLINE, & Cochrane Data Base of Systematic Reviews. Internet Google search and individual online journals were also considered. Inclusion criteria included studies published after 2000, adults over age 60 with atrial fibrillation, randomized to either anticoagulant agents, antiplatelet agents, or a combination of both. Primary end points were all stroke, ischemic stroke, or thromboembolic events. All studies were by intention to treat. Cumulatively 29,591 atrial fibrillation patients in 3 studies which utilized 31 random control trials is evaluate.

Findings Trials included multiple dosing regimens in anticoagulation agents and antiplatelet agents. Aspirin doses ranged from 50mg/daily to 1300mg/daily. Additional antiplatelet agents were also studied in various doses. Adjusted dose warfarin is mainly used for anticoagulant control. Low and fixed doses were assessed intermittently. For all stroke 2 studies reported anticoagulant treatment had superior efficacy than aspirin RRR= 0.38(95%CI: 0.18, 0.52) & RR= 0.30 (95%CI: 0.13, 0.63). Anticoagulants vs. non-aspirin antiplatelet agents RRR= 0.37(95%CI: 0.23, 0.48). A large RCT found combining agents had increase efficacy over anticoagulant agents alone with proper dosing RR= 0.33 P=0.14. INR time in therapeutic range averaged 68%.

Recommendations Combining anticoagulant and antiplatelet agents may decrease the risk of thromboembolic events in atrial fibrillation patients. Both have value in decreasing thromboembolic events. Patients should be treated individually based on risk factors, benefits, and patient preference. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

TABLE OF CONTENTS 3

Introduction………………………………………………………………………………...... 4

Significance & Background…………………………………………………….…………………. 5 1. Atrial Fibrillation………………………………………………………………………….. 5 2. Stroke……………………………………………………………………………………… 6 3. Oral Anticoagulants……………………………………………………………………….. 7 4. Antiplatelets……………………………………………..………………………………… 8 Research Question…………………………………………….……..………………………….…. 8

Relevance to Nursing……………………………………………………………………………… 9

Methods…………………………………………………………………..…………………….….. 9 1. Search Terms and Definitions…………………………………….…………………….…. 9 2. Inclusion/Exclusion Criteria…………………………………….……………………….… 10 3. Coding………………………………………………………………………….….…….… 11 4. Validity of Findings……………………………………………………………...…….….. 11

Findings……………………………………………………………………………………………. 12 1. Description of Study Characteristics………………………………………………………. 12 2. Description of Sample Characteristics…………………………………………………….. 12 3. Body of Findings………………………………………………….……………………….. 13

Recommendations for Nursing…………………………………………………………………….. 13

Conclusion…………………………………………………………………………………………… 15

References…………………………………………………………………….……………………. 17

Appendix A………………………………………………………………………………..….…… 20 Appendix B………………………………………………………………………………..………. 25 Appendix C………………………………………………………………………………..………. 27 Appendix D………………………………………………………………………………..….…… 30 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

2.6 million Americans currently have atrial fibrillation (Afib). The risk of developing 4 Afib rises with age. As the population ages, the rate of Afib patients is expected to double by

2020. Afib causes159,000 strokes annually with 11,555 deaths reported in 2009. Estimated healthcare costs are 2.6 billion dollars annually. Thromboembolic strokes have been treated with anticoagulant agents (warfarin) for more than 50 years. A 40% risk reduction has been illustrated Unfortunately, side effects, cost, and management are difficult. Reports confirm warfarin is within therapeutic range about 57% - 69% of the time. Aspirin, an antiplatelet, is used as adjunct treatment in patients who cannot or choice not to use anticoagulant agents and has shown an approximate risk reduction of 20% in Afib patients.

While these drugs have been studied extensively, dosing regimens have varied widely initiating concerns of efficacy involving them. New antiplatelet drugs are starting to emerge and be studied. Few studies have been done on agents available in the United States. The limited studies warrant scrutinizing to evaluate their effectiveness for prevention of Afib induced thromboembolic events.

At present recommendations remain guarded, encouraging individualized treatment tailored through careful examination of risk factors, benefits, and preferences. The intent of this paper is to analyze level 1 studies to decipher whether antiplatelet agents have the same efficacy as anticoagulants in preventing thromboembolic events in Afib patients. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Do Antiplatelet Medications Have the Same Efficacy as Anticoagulants for Preventing

Thromboembolic Events in Atrial Fibrillation patients?

Significance and Background

Atrial fibrillation

Atrial fibrillation (AFib) is the most common heart arrhythmia. It occurs when the

electrical activity of the heart becomes disorganized. The irregular contractions disrupt blood

flow making it more likely to have stagnant episodes in the heart. When blood is stagnant it

becomes thick which leads to clotting and a high risk of thromboembolism. Complications of

heart attack and congestive heart failure have also been reported (King, Dickerson, & Sack,

2002a).

There are 2.66 million Americans currently with AFib. That number is expected to

double by 2020 and rise to 12 million by the year 2050. A 10% increased risk of death within

the first 4 months of diagnosis can be anticipated, with a 7% risk thereafter. The associated

death rate of AFib, whether a primary or secondary cause, has increased over the past twenty

years (American Heart Association [AHA], 2009 & Department of Health and Human

Services [DHHS], 2010). According to the Heart Disease and Stroke Statistics 2009 Update,

approximately 11,555 deaths were directly attributed to AFib with a total mention rate of

88,000. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

As we age our risk for AFib increases. By age 40, 26% of men and 23% of 6 women will have a lifetime risk for AFib. Women acquire AFib at a mean age of 74.6 years

and men around 66.8. Studies have shown the there is no statistical difference between

Caucasians and blacks prior to age 60. At age 60 despite more risk factors, rates were

significantly lower in Blacks: age 60-69: 0.7%; age 70-79: 2.5%; and age greater than age

80: 2.4% (Noonan & True Hills, 2010).

Hospitalization rates for AFib increased 34% from 1996 to 2001. By 2006 the

hospitalization rate for a primary diagnosis of AFib was 2.5 times higher than in 1998 and as

a secondary diagnosis, it was 3 times higher (National Heart, Lung, and Blood Institute

[NHLBI] , 2009) . The AHA 2009 Update reports an approximated healthcare cost of $6.4

billion in the United States annually. Management goals include returning the heart back to

normal sinus rhythm, or if unable to, to achieve rhythm and rate control (King, Dickerson, &

Sack, 2002a). Unfortunately, current anti-arrhythmic medications have restricted

effectiveness and studies show that recurrence of AFib within 5 years is 25% (Boos, More &

Carlsson, 2003).

Stroke

Every 40 seconds an American citizen experiences a new or recurrent stroke, totaling

795,000 annually (Vemmos et al., 2006). Of these, 159,000 will be attributed to AFib. The

formation of left atrial thrombi in AFib is a cause of both major and minor strokes. Ischemia

is responsible for 87% of all strokes and AFib increases that risk 5 times over. The sequelae

can range from minimal weakness to severe impairment of mobility, cognitive function,

functional capabilities, or death. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Stroke was the primary diagnosis for 4.9% of patients hospitalized with AFib. Men had a 7 mean age of 66.8 and accounted for 44.8% of those patients. Women had a mean age of 74.6.

White admissions were 71.2%, while blacks and others had a rate of 5.6% and 20.8%

correspondingly. Although blacks have a much lower percentage, they tend to be younger

with a rate of 1.58 for cardioembolic stroke compared to whites. Hispanics had a 1.42 rate

compared to whites. The estimated direct and indirect cost for all strokes regardless of cause

in 2009 was 23 billion dollars (DHHS, 2010). Of those patients with a new diagnosis of

AFib, 71% were treated with antiplatelet medications for at least 6 months post stroke. A

staggering 24% were not offered any pharmacologic treatment at all.

Anticoagulant Medications

Use of the first oral anticoagulant (OAC), warfarin, began more than 50 years ago and

has proven to reduce stroke occurrences by an estimated 60% (Healey et al., 2008). It is the

most common anticoagulant used today and the only oral agent available in the United

States. Anticoagulants work via the clotting cascade. Warfarin inhibits the production of

vitamin K dependent clotting enzymes causing the factors to be dysfunctional and lowering

the ability of form clots. Adverse effects of warfarin may include gastrointestinal disorders,

dermatitis, urticaria, hair loss, skin necrosis, and the risk of bleeding (Gutierrez, 2008).

AFib patients with vitamin K deficiencies, bleeding disorders, uncontrolled hypertension,

and bacterial endocarditis are among those whom warfarin is contradicted. Controversies

surrounding anticoagulation for the AFib patients include fear of hemorrhage, hyper-

coagulant states, polypharmacy, impaired metabolism, impaired judgment, laboratory DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

monitoring, and dosage adjustments (Vemmos et al, 2006). Therefore, therapy is under used 8 leaving many unprotected from thromboembolic events.

Antiplatelet Medications

Antiplatelet medications have also been used for the prevention of stroke in AFib

patients. Disagreements as to the efficacy of antiplatelet drugs have been cited in studies.

One study showed that warfarin and aspirin were equal in effectiveness while others show

warfarin to be superior. Unfortunately, aspirin was studied with exclusion of other

antiplatelet medications (Saxena, R. & Koudstall, P., 2008). Aspirin is inexpensive, readily

available, and familiar to most people. It is a COX inhibitor that works by inactivating

prostaglandin H-synthase, which ultimately stimulates permanent platelet collection. Stroke

reduction rates of 19% to 22% are reported in prior studies (Hart, Pearce & Aguilar, 2007). It

is reported to avert non-disabling strokes over disabling strokes (Fuster et al., 2010). Other

antiplatelet medications such as Clopidogrel, Indobufen, or Triflusal could be viable

alternatives to more potent medications such as warfarin. Studies are currently being

performed to analyze the efficacy of these drugs. An integrative review of current literature

was conducted to appreciate whether patients with AFib who take antiplatelets are at greater

risk for thromboembolic events compared to those who take warfarin.

Research Question

Due to the continued efforts of the scientific community, more drugs are being introduced

to the market for the prevention of thromboembolic events related to atrial fibrillation.

Therefore, the research question posed is: Do Antiplatelet Medications Have the Same DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Efficacy as Anticoagulants for Preventing Thromboembolic Events in Atrial Fibrillation 9 patients?

Relevance to Nursing

With the ever increasing atrial fibrillation population it is important for the nursing

professional to understand the risks and benefits of preventing embolic strokes. Given the

task of managing the delicate balance of warfarin, it is necessary to look for alternatives that

will give patients a better quality of life with less need for monitoring and less risk of

hemorrhage. Decreasing risks will have a large impact on lowering complications of embolic

stroke. Nurse practitioners may offer evidence based treatment alternatives to patients which

will lower costs to them and the healthcare systems as a whole.

It is important to remember that new drugs are slowly making their way to the market

place. Nursing is obligated to continue to educate themselves, their peers, and patients to the

pros and cons associated with them. As of date, it is still recommended that treatment for the

prevention of thromboembolic events be tailored individually to patients (Hart, Pearce, &

Aguilar (2007) and Pérez-Gómez, Alegrı´a, Berjón, J., Iriarte,, et al. (2004).

Methods

Search Terms & Definitions

The following data bases were searched alone and in combination to extract articles for

literature review in reference to the problem statement: CINAHL Plus, MEDLINE, &

Cochrane Data Base of Systematic Reviews. Search terms included: clopidogrel and warfarin

and atrial fib* and stroke, Anticoag* and antiplat*(stroke preven*) and atrial fib Years: 2000-

2010. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Inclusion & Exclusion Criteria 10 Inclusion criteria for this problem statement included articles which were in English,

published between 2000 and 2010, adult patients with atrial fibrillation over the age of 60,

oral anticoagulants, and antiplatelets. Exclusion criteria consisted of studies published prior

to 2000, duplicated information. Originally 274 articles found. Two studies were kept for

evaluation and the remaining 272 were excluded because they did not meet criteria or were

duplicate studies. Subsequent searches included Google, and individual online journals. From

these searches, using the same search terms in varying combinations, 9 more articles were

found. One article is included in the final review of literature and the other 8 did not meet

criteria.

Themes

Comparable themes in the remaining three studies were evaluated in terms of the problem

statement. Each study included: all stroke (ischemic and hemorrhagic), ischemic stroke, and

all cause mortality. It is important to note the definition of primary and secondary prevention

in each study. In the Hart et al. study, primary prevention refers to all strokes regardless of

cause due to inconsistencies in individual trial reports. Secondary prevention includes

patients with previous stroke or TIA. Bover et al. trial used primary endpoints of ischemic or

hemorrhagic stroke, systemic embolism, acute coronary syndrome, sudden death, and death

from stroke event or severe bleeding within 30 days of original onset. Primary outcome is

set as incidence of first non-fatal or fatal disabling stroke (hemorrhagic or ischemic), arterial

embolism, or other intracranial hemorrhage. Major extra-cranial hemorrhage, hospital

admission or death of a non-stroke, vascular events, and all-cause mortality were considered

secondary endpoints. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

A variable of interest not included in study outcomes was the percentage of time the 11 international normalized ratio (INR) was within therapeutic range. Due to the nature of the

proposed problem statement all stroke, ischemic stroke, systemic emboli and time in

therapeutic range will be discussed. Comparisons of anticoagulant to placebo, antiplatelet to

placebo, anticoagulant to antiplatelet, and combination of anticoagulant and antiplatelet are

reviewed.

Validity of Findings

Studies were rated by using the hierarchy of evidence and rapid appraisal (screening)

questions set forth in Melnyk & Fineout-Overholt (2005) (appendix B). The three studies:

one meta-analysis by Hart, Pearce, & Aguilar (2007), and two randomized control trials

(RCTs) by Bover, Pérez-Gómez, Maluenda et al.(2009), and Mant, Hobbs, Fletcher et al.

(2007) were open-label, blinded reviews appraising the efficacy and safety of anti-thrombotic

therapies in atrial fibrillation patients. All analyses are by intention to treat.

Other study characteristics show an average follow up of 1.5 to 4.92 years for Afib

patients between the ages of 60 and 81.5. Women comprised 45% of the RCTs and 37.5%

(Bover et al., 2009, Hart et al, 2007, Mant, et al., 2007). Placebo or no therapy was used as

control across the board. The analyses define stroke by symptoms, neuro-imaging, or

autopsy. Undefined strokes were considered ischemic or all stroke. Ischemic strokes, all

stroke, and systemic emboli are considered primary outcomes.

A variety of methods were used to compute values. Hart et al., 2007 presents results as

relative risk reduction (RRR) or absolute risk reduction (ARR) which is computed using the

DerSimonian and Laird method. The Bover, et al. (2009) used the Kaplan-Meir method to

calculate survival curves and the Cox regression model for hazard ratio and confidence DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

intervals (CI). The Poisson exact method is used to calculate the relative risk (RR), hazard 12 ratios using the log rank method, and the Kaplan-Meir method for survival curves by Mant et

al., 2007.

Findings Study Characteristics

The Hart et al. meta-analysis has a clear focused research question studying the effect of

OAC treatment versus antiplatelet treatment of vascular events in 28,044 atrial fibrillation

patients. The RCT by Bover et al. is a long term follow-up of a portion of the NASPEAF.

The analysis was of 574 atrial fibrillation patients utilizing 400 NASPEAF study patients

were randomized to OAC therapy vs. combination of OAC plus Triflusal at 600mg/daily, or

OAC plus Triflusal 300 mg/daily, or aspirin 100mg/daily. Added to this group were 174 new

patients allocated to therapy at the discretion of their health care provider. The 2007

Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA) presented by Mant et

al., consisted of 973 atrial fibrillation patients aged 75 or greater. They were randomly

allocated to warfarin or aspirin had had a follow-up of approximately 3 years.

The Strength of Recommendation Taxonomy (SORT) (appendix C) was utilized to assess

the quality of the works as a whole. The works are valued as consistent level 1 patient

oriented outcomes with strength of recommendation “A” (Ebell et al. (2004). The findings

are recapitulated in appendix A.

Aspirin shows a stroke reduction of 19% which was only recorded in BAFTA. When

aspirin was added stroke reduction improved to 22%. Antiplatelet therapies compared to

control varied in the meta-analysis but still showed the same risk reduction. Comparatively

anticoagulants consistently showed superiority over control or antiplatelet therapies. For all

stroke warfarin showed a risk reduction of 64% in the meta-analysis compared to 30% in the DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

BAFTA trial. Examining ischemic stroke only; the effectiveness increases 67% and 48% 13 respectively. Limited use of newer antiplatelets diminishes innovative results. A significant

discrepancy is revealed when comparing all strokes RR between the meta-analysis and the

BAFTA; 34% and 19% for ischemic stroke.

Sample Characteristics

All three studies compare OAC and antiplatelet drugs. The BAFTA trial contrasted

warfarin with aspirin and found a 46% reduction in all stroke and 30% in ischemic stroke.

All stroke reduction of 39% is noted in the meta-analysis with a 52% relative risk reduction

in ischemic stroke. This however, included it multiple antiplatelet agents and other

anticoagulants which were available only in intravenous form. The Bover et al. trial produced

evidence of greater efficacy with combination therapy using Triflusal 600mg/daily combined

with OAC over OAC alone cutting event rates by 33%. Ischemic event rate us 36%. Triflusal

300mg/daily with OAC vs. OAC showed no difference. The OAC group however had a

higher incidence of severe bleeding.

A matter of concern worth considering is the percentage of time the INR was within

therapeutic range. Whereas the ranges varied study to study, the cumulative time in

therapeutic range averaged 67% in the BAFTA, 69% in the Bover et al. trial, and

undetermined in the meta-analysis. This may account for the gross difference in RR seen

between studies comparing all stroke in OAC to antiplatelet drugs.

Recommendations for Nursing

Consensus of studies has concluded that anticoagulant treatment is superior to antiplatelet

treatment in the AFib population. Warfarin has a RR= 61 (95% CI: 0.47, 0.71) over placebo, DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY while aspirin has a 19% (95% CI: 0.02, 0.34). Combining therapies has not proven any 14 benefit so far and may accentuate intracranial bleeding (Fuster, 2010). Antiplatelet agent studies are inadequate thus far to precisely address stroke prevention advantages.

30 % - 45% of paradoxical AFib patient have no associated heart disease and 20% - 25% of chronic AFib is in young adults (Fuster, 2010). Cardiac structure and function changes with age causing increased risk for AFib. Associates heart diseases with AFib include Mitral valve prolapse, heart failure, coronary artery disease, and hypertension.

Recommendations start with thwarting risk factors for AFib. Many risk factors cannot be modified such as age, gender, and genetics, but controlling others are key in preventing the risk of thromboembolic events. A list of reversible causes can be found in appendix D. One example is obesity. Obesity can increase the size of the left atrium which in turn can cause

The most common risk stratification tool used is the Cardiac, Failure, Hypertension, Age,

Diabetes, Stroke [Doubled] (CHADS2). See Appendix E. The scoring system is questionable in the intermediate risk group and should be scrutinized on an individual basis.

Treatment management is pertinent to prevent complications. See appendix F. Warfarin is an extremely powerful anticoagulant that requires constant monitoring. INR levels should be maintained 2.0 – 3.0. Too low and risk of stroke occurs and excessively high can lead to bleeding problems. Half life varies depending on genetic clotting factors and must be stopped prior to procedures. Onset is slow with a peak at 0.5 – 3 days and duration of 2 – 5 days

(Gutierrez, 2008). Patient education is imperative given the interactions with foods and other pharmaceuticals. Warfarin is available by prescription and in generic form and is moderately inexpensive at 5 mg (30 ea.) $14.00. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Aspirin inhibits cyclooxygenase (COX) in the platelet and is not reversible. Repeated 15 dosing at 300 mg is found to reduce thrombin production systemically, thereby decreasing risk of stroke. Serious side effects can occur with over dose and most common adverse problems are with gastrointestinal irritation, blood dyscrasias. Cost wise it is inexpensive and available over the counter.

Improving the quality of life for patients and taking note of patient preference should be considered gold standard in the management of thromboembolic prevention. Open dialog explaining the risk and benefits of therapy plus management guidelines need reinforcing throughout therapy.

Conclusion

A combination of antiplatelet medication and anticoagulation medication yields

an increased positive outcome for patients who need protection from the risk of

thromboembolic events related to atrial fibrillation. This combination also decreases the

risk of hemorrhage. This is based on a cumulative analysis of data and based on the

SORT. The quality is supported by the consistency in the meta-analysis and randomized

control trial’s findings that show combined therapy of anticoagulation with antiplatelet

therapy is superior to either alone; RRR = 50%. When combined, lower doses of

anticoagulation can be used thus, lowering the risk of significant hemorrhage in atrial

fibrillation patients. Great caution is necessary due to the limited study results published

thus far and recommendations should not be considered.

The research question can be both patient oriented and disease oriented in nature

the SORT table was adjusted using figure 2 of the article. The question is patient DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY oriented in the fact that proper treatment can increase patient quality of life; reduce 16 mortality and morbidity, and lower health care cost by decreasing risk of thromboembolic events. It is disease oriented in that therapy reduces blood coagulation that can improve risk of thromboembolic events but increase risk of bleeding.

Until satisfactory studies evaluating new antiplatelet agents are completed recommendations to continue individualized therapy is encouraged. Researchers should be persuaded to regiment dosing guidelines to enable a clearer representation of drug efficacy. Patients and healthcare workers should be more judicious in monitoring of INR time in therapeutic range to improve risk of stroke. The use of combination therapy may allow lower risk when issues arise with anticoagulation agents or are contraindicated. DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

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10.1016/j.ejim.2005.08.005 Appendix A

Literature Evaluation Study Design Patient Group Outcome Study Citation and Level of Key Results and Sample Size Variables Weaknesses Evidence Hart 28,044 Atrial Meta ALL STROKE: Some of the (2007) fibrillation Analysis of RCTs were of USA patients 29 RCTs(1) Adjusted-dose RRR= short duration. warfarin vs. 0.38 (95% CI: 0.18, 4 RCTs are Adjusted dose aspirin: 0.52) ongoing and warfarin vs. data was placebo n=2900 Adjusted- dose incomplete. warfarin vs. Non- RRR= If cause of Aspirin vs. aspirin 0.37 (95% CI: 0.23, stroke was placebo: n= antiplatelet 0.48) unknown it was 4876 agents: considered ischemic. Wide Adjusted dose variety of warfarin plus Adjusted- dose aspirin dosages antiplatelet warfarin vs. low RRR= therapy n= and fixed- dose 0.39 (95% CI: 0.22, 12,963 warfarin plus 0.52) aspirin:

Adjusted- dose RRR= warfarin vs. 0.64 (95% CI: 0.49, placebo: 0.74) NNT:37 primary prevention and NNT: 12 for secondary 2 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Aspirin vs. RRR= placebo: 0.19 (95% CI: -0.01, 0.35)

NNT: 125 primary prevention and NNT: 40 for secondary

Aspirin plus low- dose warfarin vs. RRR= 24 placebo:

Dipyridamole vs. RRR= 22¶ placebo:

Dipyridamole RRR= 43¶ plus aspirin vs. placebo:

All Antiplatelet RRR= agents vs. 0.22 (95% CI:0.06, placebo: 0.35)

ISCHEMIC STROKE:

Adjusted- dose RRR= warfarin vs. 0.67 (95% CI: 0.54, placebo: 0.77) 3 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Aspirin vs. RRR= placebo: 0.21 (95% CI:-0.01, 0.38)

Adjusted- dose warfarin vs. low and fixed- dose RRR= warfarin plus 0.52 (95% CI:0.41, aspirin: 0.62)

Mant 973 patients RCT (2) ISCHEMIC (2007) with atrial STROKE: United fibrillation aged Warfarin 10 Kingdom 75 or over. Aspirin 32 Warfarin RR= (n=488) 0.30 (95% CI:0.13, Aspirin (n=485) 0.63) P=0.0004 SYSTEMIC EMBOLISM: Warfarin 1 Aspirin 3 RR= 0.32 (95% CI:0.01, 3.99) P=0.36

ALL STROKE: RR= 0.48 (95% CI:0.28, 0.8) NNT= 50 primary prevention 4 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Bover 574 Atrial RCT (1) ALL STROKE (2009) Fibrillation Spain patients (OAC plus TRI HR: 1: (n=265) 600) vs. OAC: 0.33 Anticoagulant: P=0.14 (INR[2-3]) (OAC plus TRI HR: 2: (n= 155) 300) vs. OAC: 1.02 Anticoagulant P=0.957 (INR[1.9-2.5]) plus Triflusal (OAC plus ASA HR: 600mg/day 100) vs. OAC: 0.7 P=0.569 3: (n= 120) Anticoagulant (OAC plus TRI HR: (INR[1.9-2.5]) 300) vs. (OAC 3.07 plus Triflusal plus TRI 600): P=0.031 300mg/day (OAC plus ASA HR: 4: (n= 34) 100) vs. (OAC 2.09 Anticoagulant plus TRI 600): P=0.368 (INR[1.9-2.5]) plus aspirin ISCHEMIC 100mg/day STROKE:

(OAC plus TRI HR: 600) vs. OAC: 0.36 P=0.41

(OAC plus TRI HR: 300) vs. OAC: 1.44 P=0.331 5 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

(OAC plus ASA HR: 100) vs. OAC: undefined P=0.178

(OAC plus TRI HR: 300) vs. (OAC 4.04 plus TRI 600): P=0.012

(OAC plus ASA HR: 100) vs. (OAC undefined plus TRI 600): P=0.552

¶Only “on therapy” results were reported  No ischemic events were reported 1 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Appendix B

Hierarchy of Evidence Rating System

Source: Melnyk and Fineout-Overholt (2005) 2 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Appendix C

Strength of Recommendation Taxonomy (SORT)

Source: Ebell, et al. (2004) 3 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Source: Ebell, et al. (2004) 4 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Appendix D

Reversible Causes of Atrial Fibrillation

Metabolic Disorders

Surgery

Myocardial Infarction

Alcohol Abuse

Electrocution

Pericarditis

Myocarditis

Pulmonary Embolus

Pulmonary Diseases

Hyperthyroidism

Congenital Heart Anomalies

Other Heart Arrhythmias

Source: Fuster, et al. (2010) 5 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Appendix E

Source: Fuster, et al. (2010) 6 DO ANTIPLATELET MEDICATIONS HAVE THE SAME EFFICACY

Appendix F

Source: Fuster, et al. (2010)