Should We Stop Using Aspirin to Prevent a First Heart Attack or Stroke?

by Henry I. Bussey, Pharm.D.

The assistance of Robert Talbert, Pharm.D. and Roger Lyons, M.D. in developing this posting is gratefully acknowledged.

December 11, 2018

It is critically important to recognize that this discussion is about “primary prevention” (preventing a first stroke or heart attack in at risk individuals).  This discussion is NOT about “secondary prevention” (preventing a subsequent heart attack or stroke in someone who has already experienced one of these events) or about preventing complications of various procedures such as surgery or stent placement.  The data supporting aspirin for secondary prevention is much stronger and not being questioned here.

Four Recent Studies Feed an Ongoing Controversy:

Whether the benefits of aspirin in primary prevention out-weigh the risks has been an ongoing controversy for at least the last decade as documented by several postings on   The first of 4 recent studies is the focus of the most recent ClotCare posting in August, 2018.[1]  That study was a pooled analysis of 10 earlier studies of aspirin for primary prevention. The title of the posting is “Is It Time to Tailor the Dose of Aspirin for Primary Prevention of Cardiovascular Events and Cancer?”.  Then, the very next month, three new large, randomized, placebo-controlled studies provided new data that raise the question “Should We Stop Using Aspirin for Primary Prevention?”. [2-6]  The 3 new studies are known as the ASCEND, ARRIVE, and ASPREE trials.  Each trial involved a different study population and details will be summarized below. Following the publication of the 3 new studies, Paul Ridker, M.D. provided an editorial which concluded that “…the benefit-risk ratio for prophylactic aspirin in current practice is exceptionally small” and he suggested that a better choice would be to add a statin.[7]  Dr. Ridker also pointed out that of the three new studies and 11 others published since 2008, only 1 showed a difference in all-cause mortality and that difference favored placebo over aspirin in the ASPREE trial.  His comments suggest that smoking cessation and the aggressive treatment of diabetes mellitus, high blood pressure, and elevated cholesterol (especially with statins) lower cardiovascular (CV) risk to such a level that aspirin provides little further benefit.

Taken together, the 4 new studies certainly question the use of aspirin for primary prevention and they also raise questions about possible harms that have not been well documented previously.  Even so, there are issues of study design, study execution, and data analysis that may undermine the conclusions.  Therefore, the following discussion will be divided into 3 parts:

First let’s look at the key conclusions from the pooled analysis of 10 earlier studies and see how those findings relate to key findings of the 3 recent randomized trials.

Second, let’s examine some of the key limitations of these studies.

Third, let’s review key aspects of each of the 3 new randomized trials.

First – Key conclusions of the pooled analysis and how they relate to findings in the 3 new randomized trials.  [Relevant findings of the new studies are listed in brackets]

In the pooled analysis of 10 earlier trials, which included 117,279 patients, the authors suggested the following. [1]

  1. Low dose aspirin (75 mg to 100 mg daily) was effective only in patients who weighed 70 Kg or less.  [ASCEND, ARRIVE, and ASPREE used an aspirin dose of 100 mg daily. [2-6]  And in the ASCEND trial, in patients with diabetes, those weighing < 70 Kg did NOT show more benefit and, in fact, the authors indicated that the trend was in the opposite direction (but data were not presented).]
  2. Aspirin may increase the risk of sudden death in those weighing less than 50 Kg. [In the ASPREE trial of aspirin in the elderly (70 years and older), all-cause mortality was increased in the aspirin group but this harm was due mainly to more cancer deaths.  Sudden death was not evaluated.][4-6]
  3. Enteric coated or sustained-release aspirin – or alternate day dosing – may be less effective. [ASCEND, ARRIVE, and ASPREE trials used only enteric coated tablets given once daily.][2-6] 
  4. “High dose” aspirin (> 300 mg) is effective in those weighing more than 70 Kg but may be harmful in those weighing less than 60 Kg.  [ASCEND, ARRIVE, and ASPREE did not use “high dose” aspirin.][2-6]
  5. Twice daily dosing may be more effective.  [ASCEND, ARRIVE, and ASPREE used once a day dosing.][2-6]
  6. Low dose aspirin does not alter the rate of cancer in those who weigh 70 Kg or more.  [ASPREE, conducted in individuals 70 years and older, found an increase in overall mortality with aspirin which was due mainly to more cancer deaths – including an increase in colorectal cancer. [4-6] ]
  7. Low dose aspirin increases the rate of cancer in those weighing less than 70 Kg or more.  [See comment on ASPREE in #6 above.]
  8. Aspirin (any dose) appeared to reduce the incidence of colorectal cancer at 20 years of follow-up in those who weighed 50 to 80 Kg with no clear benefit outside of that range.  [See comment on ASPREE in #6 above; also it is possible that the 5 to 7 year duration of the new studies may have been too short to show any beneficial effect on reduction of cancer.]
  9. Younger (< 50 years old) women with diabetes who took aspirin had a > 2 fold increase in breast cancer and a > 4 fold increase in overall cancer rates.  [See comment on ASPREE in #6 above.]
  10. Low dose aspirin increased major bleeding up to a body weight of 90 Kg. [ASCEND, ARRIVE, and ASPREE each reported an increase in some type of bleeding although fatal bleeding and hemorrhagic stroke sometimes were not increased.][2-6]
  11. Major bleeding was increased with high dose aspirin and this risk increased even further in those who weighed more than 90 Kg.  [See note in #10 above; “high dose aspirin” was not evaluated in any of the 3 new randomized trials.]

Second – Key study limitations that may undermine the conclusions.

  1. Each study was quite large; the pooled analysis had more than 100,000 patients while ASCEND, ARRIVE, and ASPREE enrolled 12,500 [3] to 19,114 patients [4-6]. Such large studies carry the risk of identifying event rate differences that are statistically significant but not clinically important.  For example, a gastrointestinal bleeding rate that is 0.5% higher with aspirin over a 5-yr period may be statistically significant, but such a small increase in bleeding risk may not be clinically important; especially if those events were mainly mild bleeds?
  2. ASCEND, ARRIVE, and ASPREE used an aspirin dose of 100 mg once daily administered as an enteric coated tablet. The pooled analysis suggested that such a dose is too little for many (most?) patients, that the dose may be too infrequent (considering that 10 to 15% of one’s platelets may be produced daily after aspirin has left the blood stream), and that an enteric coated product may compromise any effect due to limited and variable absorption.
  3. Use of composite endpoints and assessing multiple “other” endpoints. With a composite endpoint, event rates with several of the endpoints may “dilute” or obscure a benefit or harm in another end point.  For example, if the composite endpoint is heart attack + cardiovascular death + stroke + TIA (transient ischemic attack), the finding of no significant reduction in the composite event rate may obscure the fact that heart attacks were reduced.
  4. Repeated significance testing. Most statistical tests are designed to see if a given, pre-specified endpoint is different than what would be expected to occur based on chance alone.  If one employs such a test to examine multiple endpoints, the likelihood of finding an erroneous “statistical” difference increases with each additional endpoint tested.  In several of these studies, the correct adjustment for a statistical “p” value was not made.  For example, mortality rates of 5.9% vs. 5.2% over almost 5 years were found to be statistically significant, but when the test was adjusted for multiple comparisons, the difference was no longer statistically significant.
  5. Patient adherence and “intentionto-treat” analysis”. Treatment studies can be analyzed by “on treatment” or “per protocol” analysis (evaluating only those events that happened among individuals actually adhering to the assigned treatment), or by “intention to treat” analysis (evaluating events that happened based on assigned treatment without regard to whether the patient was adhering to the treatment).  Intention-to-treat analysis is usually preferred because it is thought to be more indicative of what happens in usual practice when treating a given group of individuals, and it is a more statistically rigorous analysis.  But, a significant effect of treatment may be missed if patients do not adhere to the assigned treatment and/or if they switch from one treatment arm of the study to the other arm of the study.  In ASCEND, ARRIVE, and ASPREE, adherence was poor (approximately 60 – 70%) and at least in one study a decline in aspirin use in the aspirin study group was identified as was an increase in non-study aspirin use in the placebo group.
  6. Location of studies. The outcomes evaluated in these studies are influenced by diet, lifestyle, and other factors that vary from country to country.  Each of these trials was conducted largely or exclusively outside of the U.S. which could mean that the results do not apply to individuals in the U.S.
  7. Low baseline risk. The likelihood of demonstrating a beneficial effect of a given treatment becomes less at lower levels of baseline risk.  The observed event rates in these studies were less than one-half of the predicted risk.  This lower than expected rate of events may have been due, somehow, to the selection criteria or, perhaps, to changes that have occurred over time.  Changes such as smoking cessation, more aggressive treatment of high blood pressure, and more aggressive treatment of lipid disorders (and especially the use of statins) may explain the lower than anticipated event rates.
  8. Each study involved a different patient population. Benefits and risks of treatment in ASCEND, ARRIVE, and ASPREE may be similar or conflicting when comparing results across studies.  It is not surprising that “healthy elderly” (> 70 years old) persons in Australia may respond differently than a 40 year old patient with diabetes mellitus living in the U.K.  Therefore, it would seem reasonable for the clinician to keep in mind how various populations appeared to respond.  For that reason, the three studies will be summarized below individually.

Third, let’s review key aspects of each of the 3 new randomized trials.

  1. ASCEND [2]:
    1. Population: 15,480 patients with diabetes mellitus (DM), 40 years of age or older, living in the U.K. The predicted 5-year risk of a vascular event was low (< 5%) in 40% of the study participants, moderate (5-10%) in 42%, and high (>10%) in only 17%.
    2. Follow-up: mean of 7.4 years
    3. Benefit: First vascular event (excluding intracranial hemorrhage – ICH) – 8.5% with ASA vs. 9.6% with placebo (p=0.01) with no difference in vascular deaths, gastrointestinal (GI) cancer, or other cancers.
    4. Harm: First major bleed 4.1% with aspirin vs. 3.2% with placebo (p=0.003) – 41.3% of bleeds were GI, 21.1% “sight threatening”, and 17.2% ICH. Fatal bleeds (0.2%) and hemorrhagic stroke (0.3%) were not different between groups.
    5. Bottom line: Is a 1.1% lower vascular event rate over 7.4 yrs worth a 0.9% increase in major bleeding with no difference in vascular deaths, fatal bleeds, hemorrhagic stroke, or cancer?
    6. Notes: Analysis did not adjust statistics for multiple comparisons, adherence was 70% in both groups with aspirin use declining over time in the aspirin group while non-study aspirin increased over time in the placebo group.  75% of patients were taking a statin and those weighing < 70 kg did NOT show greater benefit and, in fact, the trend was in the opposite direction (per the authors but data were not presented).
  2. ARRIVE [3]
    1. Population: 12,546 moderate risk (10-20% 10-yr risk) in men 55 years and older or women 60 years and older – anticipated event rate was 17%. Those with DM and high bleeding risk were excluded.  Study participants were enrolled mainly from Western Europe with only 4% from U.S.
    2. Follow-up: median of 60 months
    3. Benefits: The composite endpoint of heart attack or myocardial infarction (MI) + cardiovascular (CV) death + unstable angina + stroke or transient ischemic attack (TIA) was NOT significantly lower with aspirin (4.29% vs. 4.48%) but approximately 30% of patients failed to complete the study.  When data were analyzed “per protocol” in the 60% of patients who were at least 60% adherent, the difference in the composite endpoint approaches statistical significance (3.40% vs. 4.19%, difference of 0.79%, p=0.0756) and the difference in MI is statistically different (0.98% vs. 1.84%, difference = 0.86%, p=0.0014).
    4. Harm: GI Bleeding rates were higher with aspirin (0.97% vs. 0.46%, difference = 0.51%, p<0.0007). Most bleeding events were mild and there was no difference in fatal bleeds.
    5. Bottom line: There was no difference in benefit by intention-to-treat analysis, and GI bleeding increase was small (0.51% over 5 years). But if one looks at patients who were at least 60% adherent, there was a statistically significant 0.86% reduction in MI.
    6. Notes: Approximately 30% of patients failed to complete the study and 43% were taking a statin.  Mortality was not different – 160 patients (2.55%) with aspirin vs 161 (2.57%) with placebo.  The observed event rate (<4.5%) was much less than the predicted 17%.
  3. ASPREE – this study was published in 3 parts with one reporting CV events and bleeding, another reporting mortality, and the third assessing “disability-free survival”. [4-6]
    1. Population: 19,114 “healthy elderly” 70 years and older, 90% white, 87% from Australia. 70% had 2 or more risk factors for CV disease.
    2. Follow-up: Median 4.7 yrs – stopped early because of lack of benefit.
    3. Benefits: There was no difference in CV disease. MI and Ischemic Stroke were lower with aspirin but the difference was not statistically significant.  The composite endpoint of death + dementia + physical disability was not different (21.5 with aspirin vs. 21.2 with placebo).
    4. Harm: Deaths were actually higher with aspirin (12.7 vs. 11.1 per 1,000 pat-yrs) due mainly to an increase in cancer deaths (6.7 vs. 5.1, a difference of 1.6 per 1,000 pat-yrs.).  Even colorectal cancer mortality was higher (0.8 vs. 0.5 per 1,000 pat-yrs).  Major bleeding was higher with aspirin (8.6 vs 6.2 per 1,000 pat-yrs, difference = 2.4 major bleeds per 1,000 pat-yrs, p<0.001).  Almost half of all major bleeds were GI.  ICH was 50% higher with aspirin at 2.5 vs 1.7 per 1,000 pat-yrs, difference = 0.8 per 1,000 pat-yrs.  Fatal hemorrhage was not different.
    5. Bottom line: No clear benefit vs. a risk of major bleeding including almost 1 more ICH per 1,000 pat-years. Mortality (including cancer-related and even colorectal cancer-related deaths) were statistically higher with aspirin.
    6. Notes: This study was stopped early because of lack of benefit.  The difference in overall mortality becomes non-significant if the p value is adjusted for multiple comparisons.  Mortality rates were lower than expected and when compared to a matched general population, all-cause mortality in study patients was approximately one-third of the matched population and cancer-related mortality was 49% of the matched population.  Adherence in the final year of the trial was 62.1% in the aspirin group vs. 64.1%.

Conclusion:  The risk of bleeding and, in some patients, the risk of a higher mortality rate due to cancer-related deaths, makes it rather difficult to recommend adding aspirin to other currently used measures for primary preventiondev.  However, these studies have a number of potential flaws and we do not have data to say whether a weight-based aspirin dosing regimen or a different aspirin product would yield better results.  But with very low event rates in the 4 to 5% range over several years, it is hard to imagine that a different aspirin dosing regimen and/or aspirin product would produce results great enough to warrant taking on the increased risk of bleeding and/or cancer in primary prevention.  Even so, a given clinician may encounter selected higher risk patients in whom the perceived benefit of aspirin may warrant its use.  In such an instance, I would use an unproven approach and modify the dosing regimen in 3 ways.  First, I would use a chewable aspirin formulation to minimize GI irritation and perhaps improve absorption.  Second, I would use a twice a day schedule to inhibit the function of the platelets released during the day after the day’s first dose of aspirin has been eliminated (as discussed in the pooled analysis). [1]  Third, I would use a total daily dose larger than 100 mg., especially in patients who weigh more than 70 Kg.[1]


  1. Rothwell PM, Cook NR Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomized trials. Lancet 2018; 392:387-99.
  2. ASCEND Study Collaborative Group. Effect of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018; 379:1529-39. DOI: 10.1056/NEJMoa1804988
  3. Gaziano JM, Brotons C, Coppolecchia R et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomized, double-blind, placebo-controlled trial. Lancet 2018; 392:1036-1046.
  4. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018; 379:1509-18. DOI: 10.1056/NEJMe1812000
  5. McNeil JJ, Nelson MR, Wods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med 2018; 379:1519-28. DOI:10.1056/NEJMe1812000
  6. McNeil JJ, Woods RL, Nelson MR, et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med 2018; 379:1499-508. DOI: 1056/NEJMe1812000
  7. Ridker PM. Should aspirin be used for primary prevention in the post-statin era? N Engl J Med 2018; 379:1572-74. DOI: 10.1056/NEJMe1812000



Matching funds available for donations to ClotCare

From Henry I. Bussey, Pharm.D. – November 26, 2017

Facebook has set aside $7 Million to use in making donations to qualified non-profits on Tuesday, Nov. 27, 2018. Matching starts at 8 AM ET and continues until the $7 million is matched. Any donations made to ClotCare (a qualified non-profit) on Tuesday after 8 AM ET will be matched by Facebook and PayPal until the $7 million is matched. To donate, check us out at
Thank you!

GivingTuesday (Nov. 27, 2018) and other timely opportunities to support ClotCare

November 23, 26, and 27, 2018 are important fundraising dates for anyone interested in supporting ClotCare at little or no cost.  The most unique opportunity is on the 27th, but I’ll provide a little information and describe all three below. is an independent, award-winning, free global information service that is dedicated to improving and saving lives by providing clinicians, patients, and care givers with up to date, unbiased information on how to prevent and/or treat blood clots that cause strokes, heart attacks, and other catastrophic conditions. The ClotCare service, started by Dr. Henry Bussey and his daughter, Marie, in 2000, is totally dependent on donations for its support.

Nov. 27 – “GivingTuesday”: Any donations made to ClotCare on this date through the facebook link below will be matched by Facebook and PayPal.  Facebook and PayPal provide this service without collecting any management fee;  the total amount goes to the non-profit.  This is an opportunity to multiply the impact of your donation. Check us out at and at

Nov. 23rd (“Black Friday”) and Nov. 26th (“Cyber Monday”) are especially busy online shopping days.  If you are shopping online on those dates (or at any other time), you can support ClotCare at no cost to you by using the online shopping sites of Amazon Smiles at or Giving Assistant at and selecting ClotCare as your preferred charity when you shop online.

Thank you for your consideration of supporting the ClotCare service.

Henry I. Bussey, Pharm.D.

A Contrarian’s View on the 2018 Chest Guideline for Antithrombotic Therapy in Atrial Fibrillation

Henry I. Bussey, Pharm.D.   November 8, 2018

Recently Drs. Rieser and Lindsay reviewed the changes in the new Chest guideline for Antithrombotic Therapy in Atrial Fibrillation (AF) for the iForumRx website.  Their review is available at

For those who would like to review the guideline, the complete report is:

Lip GYH, Banerjee A, Boriani G, Chiang Ce, Fargo R, Freedman B, Lane DA, Ruff CT, Turakhia M, Werring D, Patel S, Moores L, Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report, CHEST (2018), doi: 10. 1016/j.chest.2018.07.040.  (available online at

The following is my “contrarian” view. While it may be true that most clinicians may embrace the new guideline, I believe that there are several reasons why alternative and/or additional issues should be considered.  Here are five issues:

  1. Direct-acting Oral Anticoagulants (DOACs) should not be preferred over vitamin K antagonists (at least not in North American, Western Europe, Australia, and Scandinavian countries).

VKA therapy in patients with atrial fibrillation, if poorly managed, is associated with an increase (not decrease) in the risk of thromboembolism, major bleeding, and death over no treatment at all.[1,2]  However,  reasonably well-managed VKA therapy reduces stroke, major bleeding, and death far more than what has been reported with the DOACs (see table below). [1,3,4]  The guidelines identify several factors that are necessary for successful VKA therapy but they fail to point out that the absence of these factors from the DOAC studies undermine – and even invalidate – the conclusions of these studies.

The table below presents the ranges of events (% per year) reported in the DOAC trials, the event rates reported from sites that apparently address the factors that are necessary for successful VKA therapy, and the calculated event rates based on regression equations generated by Wan and colleagues. [1]

Range of event rates reported (%/yr) in the DOAC trials vs event rates from other reports.

Study Stroke Maj. Bleeding Death ICH/Hem. Stroke

VKA [5-8]

1.02 – 1.66 2.13 – 3.60 3.52 – 4.50 0.32 – 0.50 / 1.0 – 0.26
1.52 – 1.96 3.40 – 3.57 3.94 – 4.90 0.70 – 0.85 / 0.38 – 0.47
EAA – VKA[3] 0.30 0.86 0.75 NA
Sweden – VKA[4] 1.61 1.29 0.34 / NA
Wan, et al [1]* 0.96* 1.10 NA 0.26/0.15

*Data for Wan, et al are calculated using 2 equations that were developed by analyzing 38 atrial fibrillation studies for the relationship between the percent of time that the INR was in target range (%TTR) vs. major bleeding (MB) and thromboembolism (TE) events.  The regression equations MB = 10.104 – 0.120x[TTR], (p = 0.004) and TE = 8.313 – 0.098x[TTR], (p = 0.03).  Itracranial hemorrhage (ICH) and hemorrhagic stroke. (Hem. Stroke) were estimated based on their percentages of MB from the 4 DOAC trials[5-8]

Points to note in the above table:

  • The range of absolute differences in event rates between the DOAC and VKA groups are not large (even though warfarin was poorly managed in many locations – discussed below).
  • The European Action on Anticoagulation (EAA) is a network of clinics which reported on 5,939 patients with AF who had dramatically lower event rates with a VKA than was reported with either agent in the DOAC trials.[3]
  • In the Sweden report, where the mean time in the target INR range (TTR) was almost 70%, the more than 22,000 patients with an individual TTR (iTTR) of 70% or greater had dramatically lower event rates with a VKA than was reported with either agent in the DOAC trials.[4]

 Factors necessary for successful VKA therapy  [Note: From details available at this time, it appears that each of the DOAC studies were conducted in approximately 40 or more countries with a minority of patients being enrolled from North America (NA) and Western Europe (WE).  Therefore, it is likely that regional differences reported with one study apply to the other studies in some degree].

  • The Chest guideline talks about differences in VKA management in various geographical regions, but it does not seem to consider this factor when making the recommendation of DOACs over a VKA. If we look at one example – the ROCKET AF trial – we find that only 2 of 7 geographic regions (NA and WE) had TTRs > 60% while the other 5 regions had an unweighted TTR of 49% – a level at which VKA therapy tends to be harmful rather than beneficial.[9]  Evidence indicates that a TTR of < 50% results in a greater rate of major events than no treatment at all!  Furthermore, with the ROCKET-AF trial again serving as the example, the 5 (of 7) geographic regions with poor TTR also had more variable TTRs (discussed below) and were less attentive when patients experienced extreme INRs (where event rates increase exponentially).  For example, for INRs < 1.5 or > 4, the time to follow-up in NA and WE was approximately 10 days vs. three weeks in the 5 regions with poor TTR.[9]  Approximately 65% of patients were enrolled from these countries with quite poor VKA management which clearly skewed the data in favor of the DOAC.
  • The Guideline recommends monitoring each individual’s TTR (iTTR) and intervening if the iTTR is not > 65 – 70%. Such individualized monitoring and intervention was not part of the management in the DOAC trials; patients with poor INR control were allowed to continue poor therapy.  In other analyses, the 25% of patients with the poorest INR control have been shown to have a 3 to 6 fold higher rate of major events than the other 75% of patients [10] and a higher rate than with no treatment at all.[1,2]
  • The Guideline also identifies anticoagulation clinics and self-testing or self-management as measures that have been shown to improve outcomes and/or INR control. Self-testing and self-management were not utilized in the trials and, at least in the RE LY trial, fewer than 15% of patients were managed in an anticoagulation clinic.[11,12]
  • Adherence to a dosing algorithm may improve INR control and outcomes but, at least in the RE LY trial, deviation from the algorithm was identified as a problem that resulted in a higher rate of clinical events. [11,12]

Additional Considerations:

  • Intracranial hemorrhage and/or hemorrhagic stroke, although rare, were twice as high with VKA therapy. This reported difference is frequently cited as an advantage of the DOACs; but is it really?  In the ROCKET-AF trial, for example, the ICH rate with a VKA was 4 fold higher in Asian study sites (which enrolled only 6.5% of patients) than in other sites (2.5%/yr vs. 0.6%/yr).[13]  ICH was not statistically higher in the 93.5% of patients enrolled outside of Asian sites.  In other words, the significantly higher ICH with warfarin was due entirely to the extremely high rate reported in the 6.5% of patients who were enrolled from Asian sites.[13]  According to the Guideline, Asian sites had the lowest rate of TTR > 65% at 16.7%.  Furthermore, the ICH rate reported in Sweden with an iTTR > 70% [4] and even the major bleed rate reported by the EAA [3] – see table above – would suggest that the ICH rate with well-managed VKA therapy is not greater than that reported with the DOACs.
  • New approaches to VKA management: From 2008 to 2013 there were at least 7 small studies that reported improved INR control and efficiency of VKA management by combining INR self-testing with online monitoring and management.[14-20]  The TTR achieved in these 7 studies ranged from 74% to 81%.  In our own series with an overall TTR of 81%, the bottom quartile of patients had a TTR of 23% for the 6 months preceding the study, but each patient quickly achieved and maintained an iTTR > 70%.[18]  Such an approach also can eliminate the hassles, time, and expense of traditional VKA management.  One such system, which has been adopted by a network of 160 community pharmacies in New Zealand, now manages more than 6,000 VKA patients and is reimbursed by the New Zealand Health Ministry (personal communication with Dr. Paul Harper).
  • Pharmacodynamic and pharmacokinetic differences allow one to verify and adjust the intensity of anticoagulation with a VKA using the INR, and the effect can be partially or completely reversed over various time periods depending on the reversal method employed. The direct-effect and rapid offset of the DOACs is almost certainly why these agents contain a warning against self-discontinuation.  Similarly, the direct-effect and pharmacokinetic differences likely explain the substantially higher major gastrointestinal bleeding rate reported with each of the DOACs except apixaban.[5-8]


  1. Recommending that clinicians should strive for all VKA patients to have an iTTR > 65% -70% is a good start but it is inadequate and may be misleading. It should be recognized that the TTR calculation was developed by Dr. Rosendaal in the early 1990s as a way to determine what target INR ranges would produce adequate protection from clotting while minimizing major bleeding in patients with various indications.[21]  It was not intended to be a measure of the quality of anticoagulation and it is not an adequate measure of same.  For example, a patient with a stable INR between 3.0 and 3.3 would have an iTTR of 0% but would have very little additional risks compared to a similar patient with a stable INR of 2.5 and an iTTR of 100%.  Alternatively, we know that the rates of major events increase exponentially when the INR moves far out of range to “extreme values”.  Even in a patient with a high iTTR, an excursion to an INR of 10 or higher carries a risk of major bleeding and, if over-corrected, may also result in an increased risk of clotting.  Such wide swings in INR values almost certainly explain why several studies have found that event rates correlate better with measures of INR fluctuation than with the TTR.[22-24]  In my own practice, we calculate the iTTR but we place a higher value on time in an expanded range (target range +/- 0.3 INR units) and on avoiding extreme INR of < 1.5 and > 5.  It is entirely possible to have a patient with an iTTR that is well below the 65% Guideline target but may have an expanded iTTR of well over 80% with virtually no extreme INRs.  That patient has very well controlled VKA therapy.


  1. Use of the CHA2DS2-VASc Score can be misleading. The various scores for assessing stroke and bleeding risks in patients with atrial fibrillation are available at  The Guideline considered males with a score of 0 or females with a score of 1 to be “low risk” and not requiring anticoagulation.  The difference in the gender score, according to the Guideline, is because being female is not a risk factor unless the individual is over 65 years of age.  The reason I believe that the CHA2DS2-VASc score may be misleading is two-fold.  First, the calculated risk is for only one year and may give the clinician and/or the patient the misimpression that the one-year risk is the total risk.  Second, it gives only 3 age categories (< 65, 65-74, and > 75) and 2 hypertension categories (yes or no).  The Framingham scoring system has 11 age categories and 5 blood pressure categories, but it does not count heart failure or vascular disease.  So, each of these scoring systems may have its own limitations.  But let’s consider a couple of examples:  A 63 year old female with a systolic blood pressure of 125 mm Hg. would have a score of 1 pt (female) or zero if you discount the female gender because she is not yet 65.  Her estimated stroke risk would be zero or 3 %/yr by the CHA2DS2-VASc Score (depending on whether the female gender is counted) vs. 6% or 12% per 5 years by the Framingham score (depending on whether the 6 pts for being female is included).  Zero or 1.3%/yr vs. 6% or 12% per 5 years may be perceived differently.  Four years later when that same patient has turned 67 years old, developed diabetes, and has a systolic blood pressure of 155 mmHg, her CHA2DS2-VASc Score of 4 would suggest an annualized stroke risk of 4%/year vs. a Framingham score of 16 points and a 5 year stroke risk of 24%.  Again, a 24% 5-yr risk may be perceived differently than a 4%/yr risk.  As best I can, I try to give my patients a 5-yr risk estimate.


  1. Use of the SAME-TTR score is recommended but may be irrelevant in a site with good VKA management: This scoring is put forward as a way to determine which patients may or may not achieve a good iTTR.  As mentioned previously, in our experience, every patient (even those in the bottom quartile at a TTR of only 23% for the previous 6 months) can quickly achieve and maintained an iTTR > 70% if managed in a good system.


  1. Coronary artery disease and atrial fibrillation: The Guideline provides a nice update on combining anticoagulation and antiplatelet therapy in patients with stents.  But for patients without stents, one should remember that a good body of evidence shows that warfarin alone (or with aspirin) offers protection in coronary artery disease patients.  This issue is discussed in more detail at the ClotCare link: Rivaroxaban or Warfarin in Stable Coronary Artery Disease – Should the COMPASS Study Lead Us Back to the Future?



  1. Wan Y, Heneghan C, Perera R, et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: A systematic review. Circ Cardiovasc Qual Outcomes 2008; 1:84-91.
  2. Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa T-P. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011; 106:968-977.
  3. Poller L, Jespersen J, Ibrahim S (on behalf of the European Action on Anticoagulation – EAA). Warfarin or dabigatran for treatment of atrial fibrillation. J Thromb Haemost 2014; 12:1193-5.
  4. Bjorck F, Renlund H, Lip GYH, et al. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiology 2016; 1:172-180.
  5. Connolly SJ, Ezekowitz MD, Yusuf S, RE-LY Steering Committee Investigators et al. Dabigatran vs warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:113–151.
  6. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883-91.
  7. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981-92.
  8. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban vs Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2013; 369:2093-2104.
  9. Singer DE, Hellkamp AS, Piccini JP, et al. Impact of global geographic region on time in therapeutic range on warfarin anticoagulation therapy: Data from the ROCKET AF clinical trial. J Am Heart Assoc 2013, 2:e000067. doi: 10.1161/JAHA.112.000067.
  10. Veeger NJ, Piersma-Wichers M, Hillege HL, et al. Early detection of patients with a poor response to vitamin K antagonists: the clinical impact of individual time within target range in patients with heart disease. J Thromb Haemost 2006; 4:1625-1627.
  11. Van Spall HGC, Wallentin L, Yusuf S, et al. Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries; An analysis of patients receiving warfarin in the Randomized Evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 2012; 126:2309-2316.
  12. Rose AJ. Improving the management of warfarin may be easier than we think. Circulation 2012:126:2277-2279.
  13. Wong KSL, Hu DY, Oomman A, et al. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke 2014; 45:1739 – 1747.
  14. O’Shea SI, Arcasoy MO, Samsa G, et al. Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation. J Thromb Thrombolysis 2008; 26(1): 14-21.
  15. Ryan F, Byrne S, O’Shea S, et al.  Randomized controlled trial of supervised patient self-testing of warfarin therapy using an internet-based expert system. J Thromb Haemost 2009; 7:1284-1290.
  16. Harper PL, Pollock D. Improved anticoagulant control in patients using home international normalized ratio testing and decision support provided through the Internet. Internal Medicine Journal 2011; 41:332-7.
  17. Verret L, Couturier J, Rozon A, et al. Impact of a pharmacist-led warfarin self-management program on quality of life and anticoagulation control: a randomized trial. Pharmacotherapy 2012; 32:871-879.
  18. Bussey HI, Bussey M, Bussey-Smith KL, et al. Evaluation of warfarin management with international normalized ratio self-testing and online remote monitoring and management plus low-dose vitamin k with genomic considerations: a pilot study. Pharmacotherapy 2013; 33:1136-46.
  19. Bereznicki LR, Jackson SL, Peterson GM, et al. Supervised patient self-testing of warfarin therapy using an online system. J Med Internet Res 2013; 15(7):e138.
  20. Harper P, Shaw J, Harrison J, Harrison J. Evaluation of a community pharmacy anticoagulation management service utilizing point-of-care testing and online computer decision support (abstract ATT07). J Thromb and Haemostasis 2013; 11:11-12.
  21. Rosendaal FR, Cannegieter SC, van der Meer FJM, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69:236-239.
  22. Lind M, Fahlen M, Kosiborod M, Eliasson B, Oden A. Variability of INR and its relationship with mortality, stroke, bleeding and hospitalisations in patients with atrial fibrillation. Thrombosis Research 2012; 129:32-35.
  23. Razouki Z, Ozonoff A, Zhao S, Jasuja GK, Rose, AJ. Improving Quality Measurement for Anticoagulation Adding International Normalized Ratio Variability to Percent Time in Therapeutic Range. Circ Cardiovasc Qual Outcomes 2014;7:664-669.
  24. Van Den Ham HA, Klungel OH, Leufkens HGM, Van Staa TP. The patterns of anticoagulation control and the risk of stroke, bleeding, and mortality in patients with non-valvular atrial fibrillation. J Thromb Haemost 2013; 11: 107–15.


Is it Time to Tailor the Dose of Aspirin for Primary Prevention of Cardiovascular Events and Cancer?

[Or…Why I changed my aspirin dosing schedule]

Henry I. Bussey, Pharm.D., FCCP

I just read one of the most complex and confusing studies that I’ve ever read.  This well-written article was complex and confusing because of the amount of data presented and the number of endpoints, dosing regimens, and patient subgroups addressed. The data, however, are important and, I believe, should be practice-changing.  After reading the article twice and discussing it with a hematologist on the ClotCare Editorial Board, I made a substantial change in my aspirin dosing schedule; and I believe that there is a good chance that most others taking aspirin for primary prevention are taking a dose that may be ineffective and/or harmful.

If you would like to review the article for yourself, it is available at

Here are some of the key points that I got from this paper that analyzed individual patient data for 117,279 patients who were enrolled in trials of aspirin for primary prevention:

In the primary prevention of cardiovascular events:

  1. Low-dose aspirin (75 to 100 mg daily) is effective only in individuals who weigh less than 70 Kg (Hazard Ratio, HR = 0.77) with no benefit in those who weigh 70 kg or more (HR = 0.95). Furthermore, for those who weigh 70 Kg or more, there is a trend for low-dose aspirin to increase cardiovascular events if the individual has diabetes, smokes, or is at least 70 years old.
  2. Low-dose aspirin may be harmful in those who weigh less than 50 Kg. (including an increased risk of sudden death).
  3. Enteric coated or sustained release aspirin products may be less effective.
  4. Alternate day dosing may be less effective.
  5. High-dose aspirin (300 – 325 mg or 500 mg or more) is effective in those who weigh more than 70 Kg (where low-dose is ineffective), but high-dose may be harmful in those who weigh less than 60 Kg.
  6. Twice a day dosing may be desirable based on (1) the impressive reduction in cardiovascular events (HR = 0.74) among patients weighing less than 70 kg. in the ESPS-2 secondary stroke prevention trial that used a regimen of 25 mg of aspirin twice a day and (2) the theory that systemic availability of aspirin may be necessary to inhibit the 10-15% of new platelets that are released daily. Patients who weighed 70 Kg or more in the ESPS-2 did not exhibit a reduction in cardiovascular events with this regimen which led the authors of the current paper to suggest that 50 – 100 mg twice a day might be effective in heavier individuals.  Whether such a twice daily regimen would carry any bleeding risk in those weighing 90 kg or more is uncertain.

In the primary prevention of cancer:

  1. Low-dose aspirin did not alter the rate of cancer in those who weighed 70 Kg or more.
  2. Low-dose aspirin in those weighing less than 70 Kg increased cancer rates during the first 3 years of follow-up and this effect was especially evident in those with diabetes (HR = 1.32) and those over 70 years of age (HR = 1.35).
  3. High-dose aspirin seemed to have a similar impact on cancer rates as that seen with low-dose aspirin.
  4. Aspirin (regardless of dose or patient age) appeared to reduce the incidence of colorectal cancer at 20 years of follow-up in patients who weighed more than 50 kg and less than 80 Kg. No clear benefit was seen outside of that weight range.
  5. Women younger than 50 years of age who had diabetes and were taking aspirin had an especially high rate of cancer (HR = 4.35) due in part to a high rate of breast cancer (HR = 2.60).

The risk of major or significant bleeding with aspirin:

  1. Low-dose aspirin increases major bleeding up to a body weight of 90 Kg, above which bleeding risk disappears.
  2. High-dose aspirin carried an increased risk of major bleeding that not only persisted but increased at weights above 90 Kg.



Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: Analysis of individual patient data from randomized trials. The Lancet 2018; 392:387-399.

Does Warfarin Reduce Cancer Risk by 38% in Patients with Atrial Fibrillation?

Editor’s note: As far back as the mid-1970s, some believed that the anticoagulant effect of warfarin reduced the ability of cancer cells to seed (metastasize) to new locations.  At about the same time, interest started to grow in the ability of the body’s immune system to limit and eradicate cancer.  In the article reviewed below by guest authors Drs. Hawkins and Hornsby, the suggestion is put forth that it is the effect of warfarin on the immune system that may explain how warfarin may prevent the development of cancer.  Should this potential anti-cancer effect of warfarin (see table below) be considered when selecting an agent for long-term anticoagulation?

Table:  The Incident Rate Ratio (IRR) of Cancer in Warfarin Users Compared to Non-Users



Cancer Type


All Warfarin Users (n=92,942)

IRR (95% Confidence Interval)

Warfarin Users with A. Fib (n=33,313)

IRR (95% Confidence Interval)

All Types 0.84 (0.82 – 0.86) 0.62 (0.33 – 0.46)
Lung 0.80 (0.75 – 0.86) 0.39 (0.33 – 0.46)
Prostate 0.69 (0.65 – 0.72) 0.60 (0.55 – 0.66)
Breast (female) 0.90 (0.82 – 1.00) 0.72 (0.59 – 0.87)
Colon 0.99 (0.93 – 1.06) 0.71 (0.63 – 0.81)

Note:  The over-all incidence of cancer was 9.4% in warfarin users vs. 10.6% in warfarin non-users.  The IRR values were adjusted for age and gender.

Review – “Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years”

Zuri Hawkins, PharmD* and Lori Hornsby, PharmD, BCPS**

There is conflicting evidence regarding the antitumor benefits of warfarin and whether there is an association between its use and lower cancer incidence. Several studies have found lower rates of certain cancers such as small cell lung cancer and urogenital cancers while other studies have failed to find an association.1-5 The exact mechanism by which warfarin may provide antitumor benefits is not completely understood. The authors of a recent cohort trial published in JAMA Internal Medicine cite the inhibition of warfarin on AXL receptor tyrosine kinase-dependent tumorigenesis and enhancement of antitumor immune response as the potential mechanism.6 The continued uncertainty of warfarin’s benefit on cancer incidence led the Norwegian researchers to examine this association further in a large, unselected population-based cohort.

Haaland et al. utilized the Norwegian National Registry to identify a study cohort (n = 1,256,725) of individuals born in Norway from January 1, 1924 to December 31, 1954 who were living in Norway during the study period. The Norwegian Prescription Database and the Cancer Registry of Norway, both with a 99% national coverage of cancer diagnoses and prescription use, were utilized to determine cancer diagnoses and warfarin use.  The cohort was divided into 2 groups (warfarin users vs. nonusers).  Warfarin users were defined as individuals who were on warfarin for at least 6 months and at least 2 years before any cancer diagnosis. All others were considered nonusers. The study period lasted 7 years (January 1, 2006 through December 31, 2012). Within the cohort 92,942 (7.4%) were determined to be warfarin users, with a mean duration of use of 4.7 years. There were a total of 132,687 (10.6%) individuals found to have a cancer diagnosis.

Of the warfarin users, 8754 (9.4%) were diagnosed with cancer as compared to 123,933 (10.6%) in the non-users. The incidence ratio rate (IRR) was reduced in favor of warfarin users as compared to non-users for all cancer sites (IRR, 0.84; 95% CI, 0.82-0.86) as well as prevalent organ-specific sites (lung, 0.80 [95% CI, 0.75-0.86]; prostate, 0.69 [95% CI, 0.65-0.72]; and breast, 0.90 [95% CI, 0.82-1.00]). The IRR was not statistically significant for colon cancer (IRR, 0.99; 95% CI, 0.93-1.06). In patients receiving warfarin for stroke prophylaxis in atrial fibrillation or atrial flutter, as opposed to thromboembolic disease which has a known association with cancer, the IRRs were even lower for all cancer sites (IRR, 0.62; 95% CI, 0.59-0.65), as well as prevalent sites (lung, 0.39 [95% CI, 0.33-0.46]; prostate, 0.60 [95% CI, 0.55-0.66]; breast, 0.72 [95% CI, 0.59-0.87]) and significant for colon cancer, 0.71 [95% CI, 0.63-0.81].

Overall, the study concluded warfarin use has potential cancer benefits across a number of cancer sites in patients over 50 years of age. Strengths of the study include the large population size and availability of databases that encompass 99% of the study population. While limiting the potential for misclassification bias, this cannot be ruled out due to the cohort design of the study. The inability to account for potential confounders such as life-style and genetic factors are also potential limitations. Lastly, cancer diagnoses prior to the study period were unavailable resulting in some incidence of cancer diagnosis being reoccurrences.

Data from this trial displays a potential positive association between warfarin use and cancer prevention. While the findings of the study leaves clinicians with additional considerations regarding warfarin use in at risk populations especially those with atrial fibrillation or atrial flutter, over newer oral anticoagulants with benefits such as standardized dosing, clinicians should interpret the results of these findings with caution based the limitations of the trial. Further studies assessing the use of warfarin in cancer prevention are warranted.


  1. Zacharski L, Henderson W, Rickles F, Forman W, et al. Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate: Final report of VA cooperative study #75. Cancer 1984;53:2046-52.
  2. Akl E, Kamath G, Kim Y, Yosuico V, et al. Oral anticoagulation may prolong survival of a subgroup of patients with cancer: a Cochrane Systematic Review. J Exp Cancer Res 2007;26:175-84.
  3. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. NEJM 2000;342:1953-8.
  4. Kinnunen PT, Murtola  TJ, Talala K, Taari K, Tammela TLJ, Auvinen A. Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. Scand J Urol. 2016;50(6):413-419.
  5. Tagalakis V, Tamim H, Blostein M, Collet J, Hanley JA, Kahn SR. Use of warfarin and risk of urogenital cancer: a population based, nested case-control study. Lancet Oncol. 2007;8: 395–402.
  6. Haaland GS, Falk RS, Straume O, Lorens JB. Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years. JAMA Intern Med. 2017 Dec 1;177(12):1774-1780.

Author information:

Zuri Hawkins, PharmD is a PGY2 Ambulatory Care Resident at Piedmont Columbus Regional, Midtown Campus in Columbus, Georgia.

Lori Hornsby, PharmD, BCPS is an Associate Clinical Professor with Auburn University Harrison School of Pharmacy in Auburn, Alabama and Ambulatory Pharmacist at Piedmont Columbus Regional, Midtown Campus in Columbus, Georgia.

Anticoagulation Training for Clinicians, April 23-24, 2018

Henry I. Bussey, Pharm.D.

The Anticoaguation Forum has provided ClotCare with the following announcement.

Join World Experts at the Anticoagulation Forum Boot Camp | April 23-24, 2018 | The Intercontinental, Austin

 This compact 2-day meeting provides a comprehensive curriculum that covers the essential aspects of anticoagulation, disease state, and drug management. Engaging discussion around quality improvement, new agents and special situations will benefit all practitioners and daily ‘chalk talks’ will allow for attendee participation to shape the topics. Our Austin Boot Camp features more than 4 hours of content focusing on Transitions of Care, including highlights of innovative programs, patient case studies and ideas for practice improvement in all aspects of patient transition. Approximately 11.25 contact hours of education credit will be offered for Physicians, Nurses and Pharmacists.

Registration is $399. See the full schedule, faculty listing and register at:

Questioning Approval of the Watchman Device for Atrial Fibrillation.

Is the Watchman device better than no therapy?

Is FDA approval and use of the Watchman device misguided?

These are two questions that cardiologist John Mandrola, MD addressed in writing for in November, 2017. The Watchman device, which was recently approved by the FDA, was developed to block off the left atrial appendage – or “LAA” – (a sack-like structure that is off to the side of the left atrium chamber of the heart).  The idea behind the Watchman device is that in patients with atrial fibrillation (AF), the risk of stroke is based on the “fact” that most clots develop in the LAA before they are pumped out to the brain.  Adequate anticoagulation is usually very effective at preventing such clots, but some patients are not good candidates for anticoagulant therapy because of the associated bleeding risk.  The Watchman device is designed for such patients to close off the LAA and, thereby, prevent clots from forming in the LAA.  Such an approach may prevent clot-induced strokes while avoiding the need for anticoagulation. The FDA initially declined to approve the device until the results of a 2nd study became available.  In a Medscape posting (, Dr. Mandrola outlined seven reasons why he remains skeptical about the value of this new device.  The following comments are meant to summarize his assessments, but the reader is encouraged to review the entire article at the medscape link above.

Point 1:  The additional data did not change the direction of trends in that, at 5 years, ischemic (clot-based) stroke rates were still higher with the device and the apparent lower hemorrhagic (bleeding-based) stroke rate with the device may be due, in part, to an unusually high hemorrhagic stroke rate with warfarin.  The hemorrhagic stroke rate with warfarin was approximately twice as high as what had been reported in several earlier AF studies with warfarin.  Dr. Mandrola also questioned inclusion of cardiovascular and unexplained death as a valid endpoint in the trials.

Point 2: The new data do not change the net benefit calculation in that all the available data indicate a 6% major procedural complication rate.  This means that LAAC patients start off with a 6% chance of being harmed by the procedure and that risk has to be balanced against the possible benefit of therapy that may be “non-inferior” to warfarin.  By far, the most common procedural complication was serious pericardial effusion, but major bleed, ischemic stroke, and device embolization also occurred as procedure-related events.

Point 3:  The LAA is not the only source of AF-related clots from the heart, especially in those who are not good candidates for anticogulation.  Dr Mandrola points out that the idea that about 90% of AF-related clots come from the LAA has not been proven and that more recent data indicate that the sickest AF patients have higher rates of clots forming outside of the LAA.  It is precisely these “sicker” AF patients who are more likely to be candidates for a LAAC device due to being less likely to tolerate anticoagulation.

Point 4:  Use of antiplatelet agents and anticoagulants remains a concern.  Because the LAAC device is a foreign body inside the heart, usual therapy includes a period of warfarin therapy followed by antiplatelet therapy.  As Dr. Mandrola points out, the bleeding risk with aspirin in AF patients has been reported to be as high as that seen with warfarin, and in one study, almost 60% of LAAC device patients remained on anticoagulation or dual antiplatelet therapy at about one year after the procedure.

Point 5: “Stroke is a systemic disease”.  AF produces structural changes in the heart and blood components that lead to increased clotting risk.  Insertion of a LAAC device does nothing to reverse or correct these factors that increase the risk of clots.

Points 6 & 7:  I chose to combine these last two issues because they both are related to statistical methods.  The first point Dr. Mandrola makes is that the authors used Bayesian statistical methods which he indicates are based on “evidence or beliefs about something”.  My “take” on his discussion is that the analysis following the 2nd study may have been biased by the authors’ beliefs or views of the data from the first study.  The second point, is that the non-inferiority limits were set so wide that it is possible that outcomes with the Watchman device could have been almost 5 fold worse than the warfarin outcomes and still the analysis would have met the non-inferiority limits.

So, what’s the “bottom line”?  Dr. Mandrola concludes that “… we have no RCT-level evidence that LAAC is better than no therapy.”  (and) “… to stretch the available evidence from Watchman vs. warfarin and conclude that it is worth exposing anticoagulation-ineligible patients to an invasive, unproven preventive procedure is misguided.”

How Should We Prevent Blood Clots Following Arthroscopic Knee Surgery?

Cynthia’s Story and a Limited Discussion of the Literature

Henry I. Bussey, Pharm.D., FCCP

Cynthia, who lives in Florida, contacted out of a desire to share her story and to let others know how her surgeon changed his practices after her experience.  Following her story is a short over-view on whether arthroscopic surgery warrants anticoagulant prophylaxis and, if so, what form of prophylaxis should be used.

Cynthia’s story (with limited edits) starts here:
I am 61 years old female and was in good health.  In 2016, during my Zumba class I twisted my left knee and both felt and heard a crunch! I had had an ACL (anterior cruciate ligament) repair done on that knee many years before so I figured it was another ACL injury. I lived with the swelling and pain for several months and then finally decided to see an orthopedic doctor who had done my husband’s knee replacement. The xray confirmed a pretty severe tear in my meniscus and the doctor recommended arthroscopic surgery to remove the torn area of the meniscus. The doctor put me on a baby aspirin three times a day. At a week after the surgery I started feeling like I was coming down with the flu and had fatigue, chills and a low grade fever. I did not notice any unusual swelling but I did have foot cramping which felt like my toes were bending backwards. The third day of my “flu” my husband had to leave to visit his folks out of state. I remember him standing by the bed asking if he should stay because I wasn’t feeling well, I told him to go since his dad was ill. My daughter and her husband were living with us at the time so at least I wasn’t by myself. That was Saturday, a little over a week after the surgery. That night my daughter checked in on me and asked if she needed to take me to the ER and I told her no I was fine, though I was feeling worse. At around 2:30 am I rolled over and felt a sharp pain on my right side. When I breathed in I also felt it. I Googled my symptoms and didn’t see anything that suggested a blood clot. The only thing I saw was the possibility of it being shingles! So there I was wide awake thinking I was coming down with shingles. I got up and took myself to the ER not waking my daughter. I thought it was going to be a quick visit just to get a shingles shot, but when I mentioned to the ER physician I just had knee surgery his face turned white and they immediately took blood for a d-dimer test which came back positive. The CT scan showed a very large embolism blocking the whole right lung and a smaller one in the lower left lung. I was hospitalized for six days, and have been back in the hospital six times since then with tachycardia and blood pressure problems. I’m fairly stable now but do not feel quite the same as before, and look and feel much more tired.  Depression is also a battle. I lost my job and my life has forever changed. Doctors are amazed I survived the attack and without any obvious heart damage, but now I feel I will be spending the rest of my life trying to figure out why. To anyone contemplating minor knee surgery, make sure you are on a better clot prevention regimen than baby aspirin. My surgeon changed his protocol based on what happened to me and now uses low molecular weight heparin (such as enoxaparin) or warfarin (brand name Coumadin) and compression stockings for patients getting minor knee surgery.

Comment on Cynthia’s story:  In retrospect, because she had pain and swelling for an extended period of time before going to her doctor, it is possible that she may have developed a blood clot prior to the surgery.  An injury as mild as a sprained ankle can increase the risk of developing a blood clot and the swelling may result from – or increase the risk of having – a blood clot.  After surgery, her foot cramping, fatigue, chills, low grade fever, and a sharp pain upon breathing in are consistent with the signs and symptoms of a deep vein thrombosis (DVT) leading to blood clots in both lungs (bilateral pulmonary emboli or “PE”).  I suspect that she also had an increase in heart rate and breathing rate which are also signs of a PE.  Having a PE is a life-threatening event that should be treated as a medical emergency.  If she had been more aware of the risk and the signs and symptoms of DVT and PE, perhaps she might have sought medical attention earlier and received treatment before the condition progressed as much.  Her subsequent hospital admissions for tachycardia (fast heart rate) and “blood pressure problems” raise concerns about a related possible complication.  With large or multiple PEs, damage to the lungs may result in an increase in the blood pressure in the lungs which, in turn, can overload the right side of the heart and lead to chronic lung and heart conditions.  Hopefully that is not true in Cynthia’s case.

Discussion of DVT and PE prevention in arthroscopic knee surgery:  There is an old country western song that says when you look down into the ole swimmin’ hole, what you see depends on where you stand, how you look, and what you want to see.  Those words apply perfectly to the issue of using anti-clotting drugs to prevent DVT and PE in arthroscopic knee surgery.  Cynthia and her surgeon apparently now are convinced that patients undergoing arthroscopic knee surgery require more aggressive anti-clotting therapy than aspirin.  But the 2012 Chest guidelines recommend no such therapy – not even aspirin – for patients like Cynthia (see ).  Those who favor anticoagulation focus on the potential for blood clotting events to occur, and the fact that they may be fatal or life-altering, in patients who are usually relatively young and healthy.  Imagine the emotional and psychological impact if Cynthia’s family had found her dead the next morning from a fatal PE.  So what about those who advocate for not using any prophylaxis?  Those individuals will point to the relatively low incidence of DVT & PE with such surgery, the fact that most DVTs are limited and can be treated, and the fact that anticoagulation carries a substantial risk of hemorrhage.  Hemorrhage can be life-threatening and/or it can lead to other complications such as infection and repeat surgery.

As one expert in this area (Dr. Joe Caprini) once said, clinicians make treatment decisions based on data, experience, and emotion; but the most influential of these is emotion.  The above comments illustrate how experience and emotion can factor in to treatment decisions, but what do the data show?

In 2008, what I believe is the largest and best randomized study of DVT and PE prophylaxis in arthroscopic knee surgery was published and is summarized in a ClotCare posting at  With more than 1,300 low risk, young patients randomized to a low molecular weight heparin (LMWH) for 7 days or graduated compression stockings (GCS) following arthroscopic knee surgery, the incidence of DVT & PE was reduced from 3.2% with GCS to 0.9% with LMWH.  The difference was even greater (5.1% with GCS vs. 1.7% with LMWH) in the approximately 50% of patients who had the meniscectomy (removal of the meniscus).  Major bleeding and clinically relevant bleeding was increased from 0.3% in the GCS group to 0.9% in the LMWH group.  A third arm of the study included LMWH for 14 days but that arm was stopped early because of safety reasons.  The main conclusions from this study was that 7 days of LMWH was beneficial in young, low risk patients and especially in those whose surgery involved meniscectomy.  Many clinicians would argue that the need for LMWH is likely even greater in older patients and/or those with additional clotting risks (such as those with a prior DVT or PE); but those patients were excluded from this study.  In the face of the above data, what is the argument not to use LMWH?  Besides the financial cost of such therapy for all patients, the incidence of the most feared clot (PE) was low and not different (0.3% in each group) while the risk of major and clinically relevant bleeding was increased three fold with LMWH (0.3% vs 0.9%).  Furthermore, the difference in DVT and PE between the two groups was due to symptomatic, distal DVT.  In general, distal (below the knee) DVT carries a low risk of PE and, if symptomatic, then the condition is more likely to be identified and treated.  If we can identify and treat the majority of individuals who develop a symptomatic distal DVT, then it becomes harder to justify exposing all patients to the expense and bleeding risk of LMWH therapy.

More recently (2014), there have been 2 reviews and one meta analysis on the question of DVT & PE prophylaxis in arthroscopic knee surgery ( and  One review concluded that there is no consensus on how to prevent blood clots in these patients and suggested that each patient needs to be managed on a case by case basis.  The review and meta-analysis focused on proximal (above the knee) DVTs which are known to carry a substantially higher risk of PE than distal DVT.  Key findings from that analysis were (1) that proximal DVT rate is low regardless of whether LMWH is used (4 in 2,184 patients, 0.18%) or not (29 in 1,814 patients, 1.60%), (2) that LMWH reduces the incidence of proximal DVT from 1.60% to 0.18%, and that LMWH reduces the percent of all DVTs that are proximal (29 of 136, 21.3% vs. 4 of 36, 11.1%).  These values are consistent with the study discussed above and at the ClotCare link listed.  So the question is more or less then same – does the limited benefit seen in approximately 2% to 3% of patients justify exposing all patients to the cost and risks of LMWH?  I believe it is fair to say that the decision is a judgement call which reasonably should be influenced by the type of surgery being performed, the age of the patient (since clotting risk increases with age over 50), and other risk factors the patient may have.

But all of the above has been about LMWH… what about aspirin as was used in Cynthia’s case?  Although the Chest guidelines cited above provide a “soft” recommendation for aspirin use in some orthopedic surgeries, the data, in my opinion, are not convincing and many clinicians are reluctant to embrace aspirin for this indication.  But what about in arthroscopic surgery in particular?  I was able to find only one study that had examined this question (see  This study described results in 66 such patients who received 325 mg of aspirin daily for 14 days vs. 104 patients who received no prophylaxis.  Patients were examined for clots by ultrasound at 10 to 14 days post operatively.  No DVTs were found in either group.  It is difficult to know what to make of these findings.  It certainly is difficult to conclude that aspirin is beneficial when the outcomes were the same as with no prophylaxis.  Perhaps the study, with 170 patients was too small to identify any DVTs or perhaps some other measures or surgery technique at this single site reduced the DVT risk.  It is also feasible that the ultrasound testing missed finding clots that were there.  Ultrasound is less reliable for clots below the knee and, in fact, in some settings ultrasonographers are taught not to even perform the test below the knee.

So what’s the bottom line?  It seems reasonable to me to consider the risk of the specific surgery being performed, any additional bleeding or clotting risks the patient may have, and have the patient and clinician(s) make an informed, individualized judgement.  In addition, as in Cynthia’s case, it would seem wise to be sure that the patient is aware of not only the risks of DT &PE, but also the signs and symptoms of DVT and PE, and what to do should the signs and/or symptoms develop.  In Cynthia’s cases, she ended up doing the right thing (going to the ER) for the wrong reason (she thought she had shingles, based on her “Google diagnosis”).


Stroke: A Caregiver’s Story

How Is Caregiving for a Loved One Who Has Had a Stroke?

Diane Shares Her Story of Caring for Her Husband, Bob

The “MyTherapy” blog invited ClotCare to share the following post in support of World Stroke Day, which is October 27th.

For patients at risk of stroke who do not adhere to their therapy, I often will try to impress upon them how devastating a stroke can be to their life and lifestyle.  But I frequently do not address how a stroke may affect their loved one; Diane’s story (pasted below), however, illuminates this issue.

From MyTherapy

Each year, over three-quarters of a million people have a stroke in America. The impact of a stroke affects the life not only of the individual concerned, but those of friends, family, and loved ones, who often take on the role of caregiver. The responsibilities this sudden change entails are emotionally and physically demanding, and support can be difficult to find. As World Stroke Day 2017 arrives this weekend, Diane from The Pink House on the Corner shares with us her story of caregiving for her husband, Bob, whom she chose to bring home following his stroke.

A guest post by Dianediane-and-bob-at-the-beach-title

In 2010, my husband, Bob, suffered a massive stroke post-surgery. After a two-month hospitalization, he was transferred to an Acute Rehab Center where he was pronounced, as the doctor put it, “nursing home material”. Bob was 52 years old — not “nursing home material.” It was true that Bob could not walk, talk, swallow, could not stand, and had to be transferred from hospital bed to wheelchair with a Hoyer Lift. Still, I was adamant to take him home. In my mind, nursing homes were for the old, sick, dying, and Bob was none of these.

The doctor, against my wishes, proceeded with the admission process to a nursing home. Imagine my surprise when a representative from a nursing home showed up at the hospital, armed with a glossy brochure and a sales pitch about the facility that was so great, they even tried to provide 3 “units” of therapy a day. Though, of course, that depended on staffing.

A “unit” of therapy turned out to be 15 minutes. That would mean Bob would get 15 minutes of physio therapy (PT), 15 minutes of occupational therapy (OT), and 15 minutes of speech therapy (ST) each day (maybe). When I refused, I was told they didn’t need my permission — it was out of my control.

Of course, I argued. With the doctor, the case manager, all the way up to the director of the hospital, without luck. My fear was that Bob would not last long in a nursing home with a patient/nurse ratio of 8 to 1. He would not recover with 3 “units” of therapy (maybe) per day. I could give him better care at home.

Then a “miracle” happened. The nursing home wanted $3,000.00 before Bob could be admitted. I told them I didn’t have the money. Sometimes it pays to be poor. Bob was discharged, in my care, on New Year’s Eve 2010.

The realities of caregiving

I had no idea what I was getting myself into.

Me: who never changed a baby’s diaper.

Me: now the sole caregiver of a 6’3″ man who was incontinent, could not walk or stand, had a feeding tube inserted in his stomach, had aphasia and could say only three words: “no,” “radio,” and “window.”

Me: with expectations that there was “help” out there for at-home caregivers.

I did contact every agency that I could find, only to be told that Bob did not qualify for programs. He was too young, because he was under 65. He was too old, because he was over 21. We were “too rich,” as Bob’s social security disability (SSD) check was $200.00 over the income limit. I did manage to get a wheelchair ramp for the house, provided by one charity. I did get him wheelchair transport through the county bus system. I did find a financial aid program through a not-for-profit hospital that paid his co-pays for outpatient rehab. I did get help for the first month through Bob’s insurance.

We had a nursing assistant (CNA), for changing and bathing, and a nurse to teach me how to manage his meds, his feeding tube, and how to work the nightly feeding pump. But after four weeks, insurance ran out and I was on my own. I was not prepared that much of caregiving involves bodily fluids: adult diapers, urinary incontinence, daily laundry – all of which was overwhelming. I remember, that first week sitting on the back porch late one night behind a heap of urine soaked bedsheets, crying and wondering if I was really able to pull this off.

No one told me about condom catheters – I found this out a year or more later. These helped both Bob’s comfort and my cleaning up after him. No one explained that the feeding tube was not “permanent” and should be changed out every 8 weeks – this I discovered on my own, much later, and if I had known this it would have saved us countless trips to the ER for a clogged tube, and countless hours on my own unclogging the tube.

God bless the nurse who told me it was not necessary to have a daily bowel movement. The hospital had discharged Bob on a daily laxative, which meant constant diarrhoea. This nurse taught me “bowel movement management,” giving laxatives only when necessary.

The emotional strain

One of the hardest and most heart-breaking tasks was trying to keep his therapy going – I would take him to PT, ST, OT three times a week, pushing him there in his wheelchair, and though he showed improvement (being able to walk holding onto the parallel bar), the therapy was ended for “no functional improvement.” So, I had a railing installed in our hallway where Bob could practice walking, with me pushing the wheelchair behind him, and holding him up with a gait belt. I developed our own speech therapy and we practiced daily. I did this after the speech therapist insisted on using pictures for him to point at and teaching him gestures. Bob was good at repeating things and I used his ability; I would say a sentence, and he repeat it. I did his range of motion to keep his paralyzed arm and leg from freezing up. I bugged his primary care doctor every six months for a new script for outpatient therapy where they have special equipment, things we didn’t have at home. Each and every time, it was like starting from “square one,” and the insurance would stop after 8 weeks for “no functional improvement,” which never failed to shock me.

Another shock was the way people treated Bob post-stroke. “Baby talking” to him as if he were a child or an idiot. Talking over his head, to me, as if he wasn’t in the room. Shouting at him – as if he couldn’t hear. The friends and family who fled – as if stroke is contagious. Bob was still the same person just trapped in a disabled body. I wanted people to treat him with respect. Speak to him normally. Include him in conversations. Have patience as it sometimes took him time to respond. To listen. Visit. Make a phone call. Only a few did. I am grateful for those few.

There were other battles too, fighting for adequate pain medication, fighting for medical equipment and supplies, including a power wheelchair – the doctor insisting that Bob couldn’t manage it, and me arguing to at least let him try. That doctor, finally, ordered a powerchair, on the condition that it had an attendant control so that I could “drive” it. The first time I attempted to “drive” it, I plowed Bob straight into a wall. When Bob took control, he zoomed around the room.

I learned over the years to stick to my guns, follow my gut, and fight for my man.

The ups and downs of caregiving

Caregiving is hard. Frustration, anxiety, stress all build up. You find yourself crying, screaming, angry (Why us? Why me?). There is no time to take care of yourself, to sort out all these emotions. So you take a deep breath. Tough it out. Ignore that cold that doesn’t go away. Or that suspicious looking mole. Cut your own hair. Hope for the best and concentrate on caring for the one you love.

Then there’s grief. Grief over the loss of the man he once was and would never be again. Grief over a relationship that has changed from equal partners to caregiver/patient.

Blogging was one way I was able to vent/rant about the frustrations and anxieties of caregiving. I started my blog shortly after Bob came home. It was the one thing I could do for myself, steal 15 minutes a couple of times a week. I began blogging to keep my “hand” in writing (my profession) and to keep our family and friends informed, but strangely it turned into something else. I didn’t realize there is a whole “stroke community” out there, where I “met” stroke survivors and caregivers around the world and appreciated their support, their stories, and just knowing that we were not alone on this journey.

Caregiver burnout is real. There were many days when I felt I just could not “take it” any longer. Nights crying on that back porch then wiping away the tears and returning to my duties, putting on a smile for Bob’s sake.

All that said, I wouldn’t change a thing (well, except for the stroke part). I am glad I was able to care for Bob at home.

I cherish memories of quiet nights, watching a movie, holding Bob’s hand. Memories of “hand dancing” to a song on the radio. The nightly I love yous called to each other across the room. The way he would sing while doing his therapy exercises. The triumphs, like the first (and only) time he was able to stand up with a hemi-walker. Every new muscle movement he regained.

I deeply admire his courage and strength and motivation to never give up, never stop trying. To accept the things he could not change with a shrug and an “oh well.” Near the end of his life, though he was still not able walk or swallow, he could “tool around” (his words) in his powerchair and speak entire sentences. I’m sure he would’ve never accomplished those things in a nursing home.

Bob was able to spend his last five years in the comfort of his own home, with his two beloved cats, our dog, and with me by his side. For that, I will always be grateful.

Bob passed away on May 28th, 2015. We would like to thank Diane for contributing this guest post.

Enter your email address to follow this blog and receive notifications of new posts by email.