Atrial fibrillation means an irregular heart beat (arrhythmia) in which the upper chambers of the heart, the atria, contract chaotically rather than in coordination with the ventricles. Non-valvular atrial fibrillation (NVAF) refers to the 95% of atrial fibrillation cases of people who do not have mitral valve disease or an artificial heart valve in place. According to the most recent projections, 6.9 million people in the USA have NVAF in 2015.(1) The incidence increases with age, with the average age about 75-years-old.(2) In 2015, about 1.5 million Americans will be newly diagnosed with NVAF, rising to about 2.2 million by 2024.(1)
As a consequence of NVAF, blood may stagnate in parts of the left atrium, sometimes leading to the formation of thrombi (similar to clots, only thrombi remain within blood vessels). A left atrial thrombus may break loose and travel to the brain, causing an “embolic” stroke. “Embolic” refers to a thrombus that travels within blood vessels from one part of the body to another (e.g., heart to brain). A thrombus originating in the heart may also embolize and travel to other organs (e.g., kidney, liver, arm, etc.) and cause harm from lack of blood flow.
Patients with atrial fibrillation have an increased chance of an embolic stroke. The risk of embolic stroke in atrial fibrillation patients ranges from <2%/year to >15%/year depending on their age and cardiovascular risk factors. Researchers have standardized the measurement of cardiovascular risk in patients with NVAF with “CHADS2” scores (an acronym for congestive heart failure, hypertension, age ≥75, diabetes mellitus, and prior stroke or transient ischemic attack). CHADS2 scores of 0, 1, and ≥2 mean low risk, moderate risk, and high risk, respectively.(3) A patient’s risk of embolic stroke from NVAF goes up each year, as does the risk of anticoagulant drugs causing major bleeding.
Since antithrombotic drugs (anticoagulants like warfarin (Coumadin) and platelet inhibitors like aspirin) make it harder to form thrombi in the heart or elsewhere, these blood thinning drugs may theoretically reduce the risk of embolic stokes caused by thrombi traveling to the brain. Hypothetically, blood thinning or antithrombotic drugs may prevent strokes in patients with atrial fibrillation. However, a drug that may theoretically work for a therapeutic purpose may not provide a net overall benefit to patients. Indeed, it may do net harm. For example, side effects (in this case, major bleeding) may completely negate any benefit of the drug.
Before critiquing the randomized controlled trials (RCTs) testing the efficacy and safety of antithrombotic drugs (anticoagulants like warfarin, dabigatran (Pradaxa), rivaroxaban (Xarelto) apixaban (Eliquis), and savaysa (Edoxaban)) and platelet inhibitors like aspirin) for people with NVAF, let’s look at an informative study concerning the incidence of strokes before and after warfarin became commonly used to prevent strokes.
In the USA from 1988 to 1999, the dispensation of warfarin from pharmacies increased 4.4-fold(4) and, from 1998 to 2004, the number of dispensed outpatient prescriptions for warfarin increased from 21 million to nearly 31 million.(5) By 2007, dispensed outpatient prescriptions for warfarin were up to about 35 million. From 2007 to 2011 the sales of warfarin declined by about as much as the sales of dabigatran (Pradaxa), a “novel oral anticoagulant” approved by the FDA in 2010, increased.(6) Since 2011, rivaroxaban (Xarelto) apixaban (Eliquis), and savaysa (Edoxaban)) have also received FDA approval for the indications of NVAF and venous thromboembolism (deep venous thrombosis and pulmonary embolus).(3, 13) Novel oral anticoagulants now constitute the majority of prescribed anticoagulant drugs for atrial fibrillation patients.
In a study from the greater Cincinnati, Ohio area from 1988 to 1999, Dr. Matthew Flaherty and colleagues found the annual incidence of anticoagulant drug associated intracranial hemorrhage (AAICH) increased 5.5-fold (The annual incidence of AAICH per 100,000 persons was 0.8 (95% CI 0.3 to 1.3) in 1988, 1.9 (1.1 to 2.7) in 1993/1994, and 4.4 (3.2 to 5.5) in 1999, P < 0.001 for trend). Among persons aged > 80, the AAICH rate increased from 2.5 (0 to 7.4) in 1988 to 45.9 (25.6 to 66.2) in 1999 (p < 0.001 for trend). This was due primarily to warfarin use for NVAF patients. Cardioembolic stroke incidence data in the greater Cincinnati, Ohio area over the later part of that time frame did not change significantly (1993/1994: 31.1 / 100,000 versus 1999: 30.4 /100,000, P = 0.65).(4)
Given the above disturbing study, RCTs of warfarin versus placebos or no drugs need to be methodologically sound and have really convincing outcomes for us to accept the risk of major bleeding in people with NVAF. To set the stage for reviewing the warfarin versus placebo RCTs, let’s begin with the trials concerning the weaker blood thinner and platelet inhibitor, aspirin.
Aspirin for Stroke Protection for Patients with NVAF
A Cochrane systematic review of the original RCTs comparing aspirin with placebo for patients with NVAF found that aspirin prevents about 25% of strokes and has much less bleeding that with warfarin.(7)
After a rigorous assess of the RCTs, my systematic review of aspirin and warfarin to prevent strokes in patients with atrial fibrillation, published in Medscape General Medicine in 2003,(8) concluded: “Given the risk and cost of warfarin and its unknown efficacy compared with aspirin, aspirin should be preferred over warfarin in non valvular atrial fibrillation (NVAF).” Dr. Fiona Taylor and her colleagues from the Bristol Heart Institute published another systematic review of warfarin versus aspirin or placebo in the BMJ in 2001 that had a conclusion similar to mine, “The heterogeneity between the trials and the limited data result in considerable uncertainty about the value of long term anticoagulation compared with antiplatelet treatment. The risks of bleeding and the higher cost of anticoagulation make it an even less convincing treatment option.”(9)
References to these 2 systematic reviews that challenged the efficacy and safety of warfarin for atrial fibrillation patients were conspicuously omitted from the NVAF treatment guidelines of the American Heart Association/American College of Cardiology /Heart Rhythm Society (AHA/ACC/HRS) in 2014 (3) and the American College of Chest Physicians 2011.(13) Only systematic reviews that favored anticoagulants for NVAF were included.
While the AHA/ACC/HRS guidelines formerly recommended aspirin for low-risk people with atrial fibrillation, the 2014 AHA/ACC/HRS guidelines stopped recommending aspirin because of lack of demonstrated evidence of efficacy and concerns about safety.(10) However, the 2011 American College of Chest Physicians NVAF guidelines still suggested aspirin for low-risk patients.(3)
What was new regarding aspirin for stroke prevention for atrial fibrillation?
In 2006, an RCT of low-risk NVAF patients (CHADS2=0) in Japan comparing aspirin with no treatment provided convincing evidence to the investigators that aspirin likely does harm in low-stroke-risk patients. The study was stopped early because the rate of primary end point events (ischemic strokes and systemic emboli) in the aspirin group was non-statistically significantly higher than the control group (aspirin: 3.1% per year, versus no drug: 2.4% per year; RR: 1.24, 95% CI, 0.70 – 2.20, P = 0.46). Treatment with aspirin was also associated with a trend towards increased risk of major bleeding (aspirin group: 7 patients; control group: 2 patients; P=0.101).(11)
I agree with the AHA/ACC/HRS atrial fibrillation guidelines that aspirin is not proven effective or safe as stroke prevention in people with atrial fibrillation at any risk level.
Warfarin for NVAF Patients with Low Cardiovascular Risk
No RCTs of warfarin versus placebo restricted NVAF patient enrollment to patients at low risk for stroke or other adverse cardiovascular events. One RCT reported on a subgroup of 194 patients who were younger than 75 years and had no history of hypertension, stroke, TIA, or diabetes (i.e., low risk or CHADS2 = 0).(12) This RCT compared
(1) minidose warfarin (1.25 mg/d),
(2) minidose warfarin plus aspirin (300 mg/d),
(3) aspirin (300 mg/d) alone, and
(4) adjusted-dose warfarin targeting the blood test measuring the amount of blood thinning with warfarin (the INR or International Normalized Ratio) at 2.0 – 3.0.
The cumulative primary adverse event rates after 3 years were the following:
1. minidose warfarin (1.25 mg/d): 9.7% (95% CI, 3.1%-29.9%),
2. minidose warfarin plus aspirin (300 mg/d): 2.6% (95% CI, 0.4%-18.2%),
3. aspirin (300 mg/d) alone: 0% (95% CI, 0%-13.9%), and
4. adjusted-dose warfarin (mean INR=2.2): 11.4% (95% CI, 2.9%-46.1%).
While there was no placebo arm of this trial and the numbers were not large, the warfarin arms combined showed a trend towards more primary adverse events than the aspirin alone arm (warfarin arms: 6/139, versus aspirin alone: 0/55, P = 0.12). Given that the aforementioned aspirin versus placebo RCT for low-risk NVAF patients in Japan was stopped early because of a trend toward harm due to aspirin,(11) Warfarin also appears to be ineffective in preventing strokes in low-risk NVAF patients while carrying a significant bleeding risk.
I agree with the AHA/ACC/HRS and the American College of Chest Physicians (ACCP) guidelines for stroke prevention in NVAF patients which both recommend against the use of warfarin or other oral anticoagulants for patients at low cardiovascular disease risk (CHADS2=0).(3, 13) Notably, many low-risk NVAF patients are still treated with anticoagulants.
Flaws in Case for Warfarin or Novel Anticoagulants for Stroke Prevention for People with NVAF at Moderate- or High-Risk for Cardiovascular Events
A meta-analysis of 6 warfarin versus control (placebo or no drug) RCTs (n = 2854 participants ranging from low-risk to high-risk) showed an average reduction in strokes by 64% (95% CI, 49% to 74%).(14) However, there are major problems with each of these RCTs which I will detail in footnotes below:
- The Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF) in 1990:(15) (footnote a)
- The Copenhagen AFASAK study:(14) (footnote b)
- The Canadian Atrial Fibrillation Anticoagulation (CAFA) Study:(16) (footnote c)
- The Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation (VASPNAF) trial:(17) (footnote d)
- European Atrial Fibrillation Trial (EAFT):(18) (footnote e)
- The Stroke Prevention in Atrial Fibrillation (SPAF) Study:(19) (footnote f)
For people with moderate risk of cardiovascular events (i.e., age ≥ 75-years-old or younger people with a single risk factor, e.g., angina or diabetes: CHADS2=1), the AHA/ACC/HRS guidelines leave the choice of anticoagulant or no drug up to the treating physician.(3) The ACCP guidelines call for novel oral anticoagulant drugs for any person with atrial fibrillation who is ≥ 75-years-old or has a single cardiovascular risk factor.(13) Since no RCTs of warfarin versus placebo for NVAF patients reported outcomes of patients with a single cardiovascular disease risk factor, no evidence supports either of these recommendations.
For atrial fibrillation patients with 2 or more cardiovascular risk factors, both guidelines call for treatment with a novel oral anticoagulant drug (dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis) or savaysa (Edoxaban)).(3), (13) Although novel oral anticoagulants are much more expensive than warfarin for atrial fibrillation patients, they are not proven to be more effective or safer than warfarin.(20) Each of the novel oral anticoagulant drugs was approved by the Food and Drug Administration (FDA) based on “non-inferiority” RCTs.(21), (22), (23) This means that the trials demonstrated that the novel anticoagulants are not significantly less effective in preventing stroke or less safe regarding major bleeding. The FDA did not require any of the novel oral anticoagulants to be tested in an RCT against a placebo. Therefore, warfarin must have been shown to be effective and safe before even considering whether novel oral anticoagulants work for NVAF. I challenge the evidence-basis for the original FDA approval of warfarin as effective and safe for people with NVAF.
Let us refer to Table 1 to see why guidelines recommending anticoagulants for atrial fibrillation patients are not evidence-based:
- Up to 50% or more of RCT participants of 3/6 trials had low cardiovascular disease risk. Proof of benefit of warfarin in high-cardiovascular-risk patients cannot be derived from data on low-risk patients when we now suspect that warfarin does net harm in low-risk patients.
- Only about 7% of patients screened for the trials were enrolled, so the trial results were extrapolated to patients who would have been excluded for various reasons from the trials.
- The follow-up period, averaging about 1.6 years in the randomized trials, is far too short to predict the overall effect of anticoagulation on the natural history of NVAF.
- For people who develop NVAF, the median survival depends on the age group (55-64 year olds: 12.4 years, 65-74 year olds: 5.8 years, and 75-85 year olds: 1.7 years).(25) RCTs, with participants averaging 1.6 years on study, we cannot predict efficacy or safety over the course of expected survival of these people.
- Each year, the risk of major and fatal bleeding increases on average by about 7%.(24)
- With longer follow up times in the RCTs, we may find that the risk of bleeding goes up while the protection from stroke goes down.
- The AHA/ACC/HRS and ACCP anticoagulation for atrial fibrillation guidelines call for the INR to be kept in the “therapeutic range” (2.0 – 3.0).(3), (13) Low INR levels predispose to thromboses, and high levels predispose to major bleeding.
- In general clinical practice, the time in the therapeutic range is closer to 50%(26) or lower:
- For instance, in a population of 116,969 patients with atrial fibrillation followed by an insurance company between 1999 and 2005, warfarin was prescribed at some time in that period to 45% of patients.(27) Only 19% of patients receiving warfarin spent all or almost all of their time with INRs within the therapeutic range. In the entire group, there were 1.3 hospitalizations for ischemic stroke per 100 years and 1.2 hospitalizations for major bleeding per 100 years. So with less than half of patients receiving warfarin, major bleeding accounted for about the same number of hospitalizations as strokes.
- For people taking warfarin in the 6 trials in this meta-analysis, the INR levels were kept in the therapeutic range only about 58% of the time (Table 1).
- The longer patients are on warfarin anticoagulation, the greater the chance of episodes of the INR levels getting out of the therapeutic range. For instance, undergoing elective surgical procedures generally requires the temporary discontinuation of warfarin. INR drops into the subtherapeutic range may account for why the statistically significant benefit in reducing ischemic strokes, including minimally disabling strokes, was unaccompanied by any significant reduction in total deaths or vascular deaths (Table 1).
- In general clinical practice, the time in the therapeutic range is closer to 50%(26) or lower:
- “Rebound hypercoagulation” related thromboses: After stopping warfarin, the clotting proteins previously suppressed by the drug will increase dramatically to levels much higher than normal, causing an increased rate of thromboses over ensuing weeks or months. Rebound-hypercoagulation-related thrombotic events could adversely affect patients by increasing rates of pulmonary emboli :(32)
- In patients taking warfarin or another anticoagulant at the beginning of their RCTs who were then switched to placebos or no drugs, adverse cardiovascular events may have been increased due to rebound hypercoagulation occurring in the no drug treatment groups.
- RCT patients taking warfarin until the end of the trial would likely suffer rebound-hypercoagulation-related thromboses after the trial, when adverse events are no longer counted. Sufficient data have not been provided in the reports of these 6 RCTs to determine the rates of embolic stroke and other vascular adverse events in the first few months after discontinuing warfarin.
- Of ischemic strokes and systemic emboli primary events in warfarin-treated patients in these 6 RCTs, 16/21 (76%) were in patients who had INR levels < 2.0, of whom almost all had temporarily stopped warfarin. The fact that the INR was in the therapeutic range 58% of the time and 76% of ischemic strokes and embolic events occurred during below therapeutic INRs suggests that rebound hypercoagulation caused many of the strokes in warfarin-treated patients.
- For another perspective on the advisability of anticoagulants to prevent stroke in high-cardiovascular-risk patients in light of rebound hypercoagulation after withdrawing warfarin, an observational study in Ontario, Canada evaluated the anticoagulation status of patients with known atrial fibrillation admitted to hospital with ischemic strokes.(33) Patients were excluded if they had contraindications for warfarin or if they were not living independently. Only patients at high-cardiovascular risk were included (i.e., CHADS2 ≥ 2).
- For patients hospitalized with a first-ever acute ischemic stroke (n=597), 40% were taking warfarin before admission. Of those taking warfarin, 74% had a subtherapeutic INRs (< 2.0) at admission.
- For patients in this study hospitalized with acute ischemic stroke who had known NVAF and a history of ischemic stroke or TIA (n=323), 57.3% were taking warfarin before admission. Of these, 68.3% had a subtherapeutic INR at admission.
- For the vast majority of these high-risk NVAF patients with subtherapeutic INRs while having their strokes, rebound hypercoagulation could have contributed to causing their strokes.
- A population-based stroke study in the Greater Cincinnati/Northern Kentucky area looked at when ischemic strokes occurred in relationship to the withdrawal of antithrombotic medication (warfarin and aspirin). Of 2197 cases of ischemic stroke, 114 (5.2%) occurred within 60 days of an antithrombotic medication withdrawal, 61 (53.5%) of these after stoppage of warfarin and the remainder after stoppage of an antiplatelet medication. This further supports that stopping warfarin (and aspirin) cause a spike in the rate of ischemic strokes.
- Not all ischemic strokes in people with NVAF are caused by emboli from the heart.
- People with NVAF having cardiovascular disease risk factors are not immune from ischemic strokes not caused by emboli.
- People with NVAF have a rate of ischemic stroke from 2 to 7 times that of age-matched controls.(34)
- Consequently, about 1 in 5 strokes in people with NVAF is not caused by emboli from the heart. The usual atherosclerotic disease and hypertension are primarily responsible.
- So, does warfarin effectively prevent strokes in people at high risk but without atrial fibrillation?
- A Cochrane systematic review looked at antithrombotic treatment for secondary prevention of recurrent ischemic stroke after a TIA or minor stroke of presumed arterial origin and not associated with NVAF. The review concluded, “there is sufficient evidence to conclude that vitamin K antagonists (i.e., warfarin) in any dose are not more efficacious than antiplatelet therapy and that medium and high intensity anticoagulation leads to a significant increase in major bleeding complications.” (i.e., warfarin does net harm in these patients).
- A single RCT tested whether warfarin or aspirin could effectively provide primary prevention against stroke, heart attack, and death. Enrolling patients with chronic heart failure, Cleland and colleagues found that more patients randomized to aspirin were hospitalized for cardiovascular reasons, especially worsening heart failure (P = 0.044). Warfarin was no more effective than aspirin or no drug. The authors concluded, “Antithrombotic therapy in patients with heart failure is not evidence based but commonly contributes to polypharmacy.”(35)
- So, given that antithrombotic stroke/heart attack preventive treatment of high-cardiovascular-disease-risk people without NVAF is ineffective and dangerous, warfarin would not prevent ischemic, non-embolic strokes in NVAF patients. Given that about 20% of ischemic strokes in high-cardiovascular-risk NVAF patients are not caused by emboli from the heart, warfarin is harmful for about 20% of high-risk patients with NVAF.
Anticoagulant Related Bleeding in Atrial Fibrillation Patients: A Public Health Problem
The risk of major bleeding in atrial fibrillation patients attending community clinics is much higher than in the RCTs for several reasons:
- The average age of NVAF patients in community practice is 75 years old (36, 37). High-cardiovascular-risk NVAFpatients (i.e., CHADS2 ≥2) are older, perhaps averaging nearer to 80 years old. However, the mean age of patients selected by anticoagulation experts for the 6 warfarin versus placebo RCTs was only 69-years-old (Table 1).
- With major and fatal bleeding associated with warfarin increasing by 7% per year,(24) this mean age discrepancy (69-years-old versus 80-years-old) means that the bleeding risk of high-risk community NVAF patients is more than double that of all risk level patients selected for the 6 warfarin versus placebo RCTs (1.07^11 = 2.10).
- Only about 7% of atrial fibrillation patients screened for the RCTs were enrolled in the trials (Table 1). Researchers naturally selected study participants more likely to be compliant and less liable to have major bleeding.
- Whereas the rates of warfarin-associated major, fatal, and intracranial bleeding in these 6 RCTs averaged 2.2%/year, 0.13%/year, and 0.13%/year, respectively, 4 studies of NVAF patients followed from the inception of treatment in general practices showed much higher warfarin-associated rates of major bleeding, fatal bleeding, and intracranial bleeding:
Rates of oral-anticoagulant-related bleeding can be estimated based on bleeding rates from the above studies,(38, 39, 40, 41) and an audit of the prescriptions of oral anticoagulants in the USA(6) along with data on the trend in the prevalence of atrial fibrillation(1) shows that in 2015 there are about 1 million atrial fibrillation patients take oral anticoagulants each day. Utilizing this data, warfarin and novel oral anticoagulant treatment of NVAF patients account for an estimated:
- 68,000 major bleeds in the United States per year
- 12,000 bleeds that are fatal, and
- 14,000 bleeds that are intracranial.
The Cost of Anticoagulant Treatment for NVAF Patients
An estimated 1 million NVAF patients take oral anticoagulants each day.(1, 6) About 38% of anticoagulated patients receive warfarin and 62% get novel oral anticoagulants.(42) The cost of warfarin (drug, testing, and office visits) has been estimated at $545/year and for dabigatran $3000/year (no testing required).(20) So the total cost of anticoagulation for atrial fibrillation patients is about $2 billion/year in 2015. (footnote g)
The cost of 68,000 major bleeding episodes related to anticoagulation at about $45,000 per major bleed ≈ $3 billion.
Total estimated cost of anticoagulants for stroke protection in 2015 ≈ $5 billion ($2 billion anticoagulants and monitoring + $3 billion major bleeds) (footnote g).
Class Action Suit against Pradaxa for Major Bleeding
After the FDA approved Pradaxa for NVAF in October 2010, Boehringer Ingelheim Pharmaceuticals invested $464 million to market it in 2011 as a safe, effective, and convenient alternative compared to warfarin. It worked and gave Pradaxa a jump on the competitors. In 2012, worldwide Pradaxa sales soared to $1.5 billion.(44) From October 2013 to September 2014, Pradaxa, Xarelto, and Eliquis sales in the USA alone totaled about $3.2 billion.(42), (45)
Within a year of the FDA approval of Pradaxa, lawyers filed thousands of law suits against Boehringer Ingelheim for the suffering and deaths of patients from major bleeding. The attorneys consolidated many of the suits into a multidistrict litigation in the U.S. District Court for the Southern District of Illinois. A few months before the case was to go to trial in 2014, Boehringer Ingelheim announced it would pay $650 million to settle all 4000 state and federal Pradaxa lawsuits.(46) This averages about $160,000 pay out per suit.
Attorneys for the people injured by Pradaxa did not claim that the drug failed to prevent strokes in NVAF patients or did not prevent deaths or suffering from venous thromboembolism (see my previous blog: More Blood Thinners for Hillary Clinton?) Instead, they alleged that Boehringer Ingelheim willfully endangered the public through its use of deceptive marketing practices. In particular, the drug maker failed to warn doctors and patients about bleeding risks and failed to provide an anecdote for severe bleeding.(47)
The Institute of Safe Medication Practices linked Pradaxa to more deaths and injuries in 2011 than any of the 800 other drugs it reviewed.(47) In 2011, the FDA ranked Pradaxa as #1 in serious adverse events (primarily major bleeding). The FDA’s voluntary adverse reporting system in 2011 logged thousands of Pradaxa-related adverse events, including 542 bleeding deaths. In 2011, Pradaxa had about 12.5% of the oral anticoagulant market, with warfarin holding down the remainder.(6) This means there were a bare minimum of 4340 bleeding deaths due to oral anticoagulants that year. Since the FDA’s adverse reporting system is entirely voluntary, the number was undoubtedly much higher.
After a FDA review of Pradaxa that was widely criticized inside and outside of the agency, the FDA reported in 2012: “bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin…”(47)
The nonprofit group Observations Medical Outcomes Project (OMOP) – formed by the FDA, Pharmaceutical Research and Manufacturers of America (PhRMA) and the National Institutes of Health (NIH) – questioned the methodology of the FDA review and recommended that the FDA rethink its analysis. The FDA claims it is “continuing to evaluate multiple sources of data in the ongoing safety review of this issue.”(47) However, my emails to the FDA leadership, detailing my case for withdrawing FDA approval for anticoagulants for venous thromboembolism, were shunted to a pharmacist in the drug information office and ignored by the FDA decision-makers.
Pradaxa may also somehow at times increase the tendency to form thromboses. A meta-analysis of large trials comparing Pradaxa and warfarin showed an increase of about 33% in acute coronary syndrome and heart attacks in patients given Pradaxa.(48) This could represent a consequence of rebound hypercoagulation. Studies of rebound hypercoagulation on discontinuing the novel oral anticoagulants have not been done.
Perhaps the next round of lawsuits against the manufacturers of the novel oral anticoagulants should be based on the strong evidence that anticoagulant drugs do not benefit any patients with NVAF and venous thromboses.
Lifestyle Changes to Reduce the Risk of Embolic Stroke in Patients with Atrial Fibrillation
The official guidelines of the American Heart Association, The American College of Cardiology, the Heart Rhythm Society (AHA/ACC/HRS) call for lifestyle changes to prevent embolic strokes and systemic emboli in patients with NVAF.(3, 10) However, according to a report from the National Heart, Lung, and Blood Institute, studies to test lifestyle-modifying interventions for primary prevention of NVAF have not been performed.(49)
We know that deaths in people with NVAF are largely due to cardiac diseases (38%) and strokes (10%).(50) Other causes include kidney disease and diabetes.
The American Heart Association Diets (AHA) step 1 and step 2 low-fat diets (fruits, vegetables, lean meat, low fat dairy, eggs, etc.(51) is the standard offering to reduce deaths, strokes, and other cardiovascular adverse events in the USA.
However, the AHA diets are not evidence-based to work.
The Cochrane collaboration published a systematic review comparing the AHA diet with the standard American Diet.(52) This meta-analysis of 27 trials (30,901 person-years) concluded that there was no significant effect on total mortality (rate ratio 0.98, 95% CI 0.86 to 1.12) or cardiovascular mortality (rate ratio 0.91, 95% CI 0.77 to 1.07). In my view, these diets should not be recommended to patients with non-valvular atrial fibrillation.
Diets that have been shown to reduce cardiovascular disease mortality include a vegan diet,(53) Mediterranean diet,(54) and vegetarian diet.(55) Aerobic exercise, stress management, and avoidance of tobacco are also mainstays of the lifestyle to prevent cardiovascular disease.(56)
Intensive diet and lifestyle changes to reduce cardiovascular disease risk can serve as a safe and effective alternative to anticoagulant drugs to reduce risks of strokes, systemic emboli, and other cardiovascular diseases in people with NVAF.
1. Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of Current and Future Incidence and Prevalence of Atrial Fibrillation in the U.S. Adult Population. American Journal of Cardiology. 2013; 112(8):1142-1147. Available at: http://www.ajconline.org/article/S0002-9149(13)01288-5/abstract
2. Fuster V, Rydén LE, Cannom DS, et al. . American College of Cardiology/American Heart Association Task Force on Practice Guidelines et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006; 114:e257-e354. Available at: http://circ.ahajournals.org/content/114/7/700.full.pdf
3. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology. 2014; 64(21):e1-e76. Available at: http://dx.doi.org/10.1016/j.jacc.2014.03.022
4. Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007; 68(2):116-121. Available at: http://www.neurology.org/cgi/content/abstract/68/2/116
5. Wysowski DK, Nourjah P, Swartz L. Bleeding Complications With Warfarin Use: A Prevalent Adverse Effect Resulting in Regulatory Action. Arch Intern Med. 167(13):1414-1419. Available at: http://archinte.ama-assn.org/cgi/content/abstract/167/13/1414
6. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National Trends in Oral Anticoagulant Use in the United States, 2007 to 2011. Circulation: Cardiovascular Quality and Outcomes 2012 5 (5 ):615-621 Available at: http://circoutcomes.ahajournals.org/content/5/5/615.full
7. Aguilar M, Hart R. Antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischaemic attacks. Cochrane Database of Systematic Reviews. 2005; (Issue 4). Available at: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD001925/frame.html
8. Cundiff DK. Anticoagulants for Non Valvular Atrial Fibrillation (NVAF) – Drug Review. Medscape General Medicine. 2003; 5(1). Available at: http://www.medscape.com/viewarticle/448817
9. Taylor FC, Cohen H, Ebrahim S. Systematic review of long term anticoagulation or antiplatelet treatment in patients with non-rheumatic atrial fibrillation. BMJ. 2001; 322:321-326. Available at: http://bmj.com/cgi/content/full/322/7282/321?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1=taylor%2C+f&searchid=1035525351878_25602&stored_search=&FIRSTINDEX=0&resourcetype=1,2,3,4,10
10. Atrial Fibrillation Guidelines 2014. Cardiosmart.org. https://www.cardiosmart.org/Heart-Conditions/Guidelines/Atrial-Fibrillation-Guidelines-2014
11. Japan Atrial Fibrillation Stroke Trial Group. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial. Stroke. 2006; 37:447-451. Available at: http://stroke.ahajournals.org/content/37/2/447.long
12. Gullov AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med. 1998; 158(14):1513-1521. Available at: http://archinte.jamanetwork.com/article.aspx?articleid=208616
13. You JJ, Singer DE, Howard PA, et al. Antithrombotic Therapy for Atrial Fibrillation. Chest. 2012; 141(2 suppl):e531S-e575S. Available at: http://journal.publications.chestnet.org/article.aspx?articleid=1159549&rss=1&ssource=mfr
14. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet. 1989; 1(8631):175-179. Available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=2563096
15. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med. 1990; 323(22):1505-1511. Available at: http://www.nejm.org/doi/full/10.1056/NEJM199011293232201
16. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991; 18(2):349-355. Available at: http://www.ncbi.nlm.nih.gov/pubmed/1856403
17. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med. 1992; 327(20):1406-1412. Available at: http://www.nejm.org/doi/full/10.1056/NEJM199211123272002
18. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group. Lancet. 1993; 342(8882):1255-1262. Available at: http://www.ncbi.nlm.nih.gov/pubmed/?term=7901582
19. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991; 84(2):527-539. Available at: http://www.circ.ahajournals.org/content/84/2/527.full.pdf
20. Stiles S. Dabigatran Cost-Effectiveness Depends on Risk, INR Control. Heartwire from Medscape; June 07, 2011. http://www.medscape.com/viewarticle/744197
21. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2009; 361(12):1139-1151. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0905561
22. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011; 365(10):883-891. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1009638
23. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2011; 365(11):981-992. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa1107039
24. Linkins L , O’Donnell M , Julian JA , Kearon C. Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy. J Thromb Haemost . 2010; 8(10):2201 – 2207. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2010.04016.x/pdf
25. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of Atrial Fibrillation on the Risk of Death: The Framingham Heart Study. Circulation. 1998; 98(10):946-952. Available at: http://circ.ahajournals.org/content/98/10/946.abstract
26. Matchar DB, Samsa GP, Cohen SJ, Oddone EZ, Jurgelski AE. Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial. Am J Med. 2002; 113(1):42-51. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12106622
27. Walker AM, Bennett D,. Epidemiology and outcomes in patients with atrial fibrillation in the United States. Heart Rhythm. 2008; 5(10):1365-1372. Available at: http://www.heartrhythmjournal.com/article/S1547-5271%2808%2900713-3/fulltext
28. Cundiff DK. Clinical evidence for rebound hypercoagulability after discontinuing oral anticoagulants for venous thromboembolism. Medscape J Med. 2008; 10(11):258. Available at: http://www.medscape.com/viewarticle/582408
29. Sise HS, Moschos CB, Gauthier J, Becker R. The Risk of Interrupting Long-Term Anticoagulant Treatment: A Rebound Hypercoagulable State Following Hemorrhage. Circulation. November 1, 1961; 24(5):1137-1142. Available at: http://circ.ahajournals.org/cgi/content/abstract/24/5/1137
30. Sharland DE. Effect of cessation of anticoagulant therapy on the course of ischaemic heart disease. Br Med J. 1966; 2(5510):392-393. Available at: http://www.researchgate.net/publication/9128684_Long-term_anticoagulant_therapy_after_acute_myocardial_infarction._A_retrospective_study_based_upon_a_nine-year_experience_at_the_University_of_Chicago
31. Grip L, Blomback M, Schulman S. Hypercoagulable state and thromboembolism following warfarin withdrawal in post-myocardial-infarction patients. Eur Heart J. 12(11):1225-1233. Available at: http://eurheartj.oxfordjournals.org/cgi/content/abstract/12/11/1225
32. Broderick JP, Bonomo JB, Kissela BM, et al. Withdrawal of Antithrombotic Agents and Its Impact on Ischemic Stroke Occurrence. Stroke. 2011; 42(9):2509-2514. Available at: http://stroke.ahajournals.org/content/42/9/2509.long
33. Gladstone DJ, Bui E, Fang J, et al. Potentially Preventable Strokes in High-Risk Patients With Atrial Fibrillation Who Are Not Adequately Anticoagulated. Stroke. 2009; 40(1):235-240. Available at: http://stroke.ahajournals.org/content/40/1/235.abstract
34. Members C, Fuster V, Rydén LE, et al. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Circulation. 2001; 104(17):2118-2150. Available at: http://circ.ahajournals.org/content/114/7/700.full.pdf
35. Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J. 2004; 8(1):157-164. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15215806
36. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med. 1995; 155:469-473. Available at: http://archinte.jamanetwork.com/article.aspx?articleid=620157
37. Go AS, Hylek EM, Phillips KA. Prevalence of diagnosed atrial fibrillation in adults. National implications for rhythm management and stroke prevention: The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001; 285:2370–2375. Available at: http://jama.jamanetwork.com/article.aspx?articleid=193807
38. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients With Atrial Fibrillation. Circulation. 115(21):2689-2696. Available at: http://circ.ahajournals.org/content/115/21/2689.full
39. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. American Journal of Medicine. 1989; 87(2):144-152. Available at: http://www.ncbi.nlm.nih.gov/pubmed/2787958?dopt=Abstract
40. Steffensen F, Kristensen K, Ejlersen E, Dahlerup J, Sorensen H. Major haemorrhagic complications during oral anticoagulant therapy in a Danish population-based cohort. J Intern Med. 1997; 242:497–503. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.1997.tb00023.x/pdf
41. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. American Journal of Medicine. 1998; 105(2):91-99. Available at: http://www.amjmed.com/article/S0002-9343%2898%2900198-3/fulltext
42. Brown T. 100 Most Prescribed, Best-Selling Branded Drugs Through September. Medscape Medical News; November 03, 2014. http://www.medscape.com/viewarticle/834273
43. Alpert JS. The NOACs (Novel Oral Anticoagulants) Have Landed! The American Journal of Medicine. 127(11):1027-1028. Available at: http://dx.doi.org/10.1016/j.amjmed.2014.07.028
44. Mesko J. Boehringer Ingelheim to Pay $650M to Settle 4000 Pradaxa Lawsuits. drugwatch.com; May 28th, 2014. http://www.drugwatch.com/2014/05/28/boehringer-ingelheim-settles-pradaxa-lawsuits/
45. Weinstein D. Bristol-Myers Squibb sales rise, led by Eliquis and Opdivo. Medical Marketing and Media; April 28, 2015. http://www.mmm-online.com/bristol-myers-squibb-sales-rise-led-by-eliquis-and-opdivo/article/411637/
46. Pradaxa Lawsuits and Settlements. January 22, 2015. http://www.drugwatch.com/pradaxa/lawsuit/
47. Pradaxa Bleeding. Drugwatch.com; December 8, 2014. http://www.drugwatch.com/pradaxa/bleeding/
48. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: Meta-analysis of noninferiority randomized controlled trials. Archives of Internal Medicine. 2012; 172(5):397-402. Available at: http://dx.doi.org/10.1001/archinternmed.2011.1666
49. Benjamin EJ, Chen P-S, Bild DE, et al. Prevention of Atrial Fibrillation: Report From a National Heart, Lung, and Blood Institute Workshop. Circulation. 2009; 119(4):606-618. Available at: http://circ.ahajournals.org/content/119/4/606.abstract
50. Marijon E, Le Heuzey JY, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study. Circulation. 2013; 128(20):2192-2201. Available at: http://circ.ahajournals.org/content/early/2013/09/09/CIRCULATIONAHA.112.000491
51. Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines: Revision 2000: A Statement for Healthcare Professionals From the Nutrition Committee of the American Heart Association. Circulation. 2000; 102(18):2284-2299. Available at: http://circ.ahajournals.org/content/102/18/2284.full
52. Hooper L, Summerbell CD, Higgins JPT, et al. Reduced or modified dietary fat for preventing cardiovascular disease (Cochrane Review). The Cochrane Library, Issue 1, 2003. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163969/
53. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998; 280(23):2001-2007. Available at: http://jama.jamanetwork.com/article.aspx?articleid=188274
54. de Lorgeril M, Salen P, Martin J-L, Monjaud I, Delaye J, Mamelle N. Mediterranean Diet, Traditional Risk Factors, and the Rate of Cardiovascular Complications After Myocardial Infarction : Final Report of the Lyon Diet Heart Study. Circulation. 1999; 99(6):779-785. Available at: http://circ.ahajournals.org/cgi/content/abstract/99/6/779
55. Fraser GE. Vegetarian diets: what do we know of their effects on common chronic diseases? Am J Clin Nutr. 2009; 89(5):1607S-1612S. Available at: http://ajcn.nutrition.org/content/89/5/1607S.full
56. Barnard RJ, DiLauro SC, Inkeles SB. Effects of intensive diet and exercise intervention in patients taking cholesterol-lowering drugs. Am J Cardiol. 1997; 79(8):1112-1114. Available at: http://www.ajconline.org/article/S0002-9149%2897%2900058-1/abstract