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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 ClotCare.org. The first of 4 recent studies is the focus of the most recent ClotCare posting in August, 2018. 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. 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. 
- 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).]
- 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]
- 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]
- “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]
- Twice daily dosing may be more effective. [ASCEND, ARRIVE, and ASPREE used once a day dosing.][2-6]
- 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] ]
- Low dose aspirin increases the rate of cancer in those weighing less than 70 Kg or more. [See comment on ASPREE in #6 above.]
- 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.]
- 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.]
- 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]
- 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.
- Each study was quite large; the pooled analysis had more than 100,000 patients while ASCEND, ARRIVE, and ASPREE enrolled 12,500  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?
- 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.
- 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.
- 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.
- Patient adherence and “intention–to-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.
- 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.
- 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.
- 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.
- ASCEND :
- 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%.
- Follow-up: mean of 7.4 years
- 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.
- 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.
- 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?
- 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).
- ARRIVE 
- 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.
- Follow-up: median of 60 months
- 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).
- 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.
- 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.
- 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%.
- 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]
- Population: 19,114 “healthy elderly” 70 years and older, 90% white, 87% from Australia. 70% had 2 or more risk factors for CV disease.
- Follow-up: Median 4.7 yrs – stopped early because of lack of benefit.
- 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).
- 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.
- 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.
- 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).  Third, I would use a total daily dose larger than 100 mg., especially in patients who weigh more than 70 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. Lancet 2018; 392:387-99. dx.doi.org/10.1016/S0140-6736(18)31133-4
- 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
- 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. Dx.doi.org/10.1016/S0140-6736(18)31924-x
- 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
- 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
- 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
- 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
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 https://www.facebook.com/clotcare.org/
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.
ClotCare.org 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 www.ClotCare.org and at www.facebook.com/fundraisers
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 smile.amazon.com or Giving Assistant at givingassistant.org 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.
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 https://iforumrx.org/commentary/top-ten-things-every-clinician-should-know-about-2018-antithrombotic-therapy-atrial
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 https://journal.chestnet.org/article/S0012-3692(18)32244-X/fulltext#sec7.3.1)
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:
- 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. 
Range of event rates reported (%/yr) in the DOAC trials vs event rates from other reports.
|Study||Stroke||Maj. Bleeding||Death||ICH/Hem. Stroke|
|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||0.30||0.86||0.75||NA|
|Sweden – VKA||1.61||1.29||0.34 / NA|
|Wan, et al *||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.
- 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.
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. 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. 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  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]
- 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). 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. 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%  and even the major bleed rate reported by the EAA  – 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%. 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]
- 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. 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.
- 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 http://www.clotcare.com/assessing_stroke_and_bleeding_risk_in_atrial_fibrillation_consensus_statement_on_appropriate_anticoagulant_use.pdf). 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.
- 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.
- 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?
- 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.
- 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.
- 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.
- Bjorck F, Renlund H, Lip GYH, et al. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiology 2016; 1:172-180.
- 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.
- 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.
- 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.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban vs Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2013; 369:2093-2104.
- 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.
- 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.
- 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.
- Rose AJ. Improving the management of warfarin may be easier than we think. Circulation 2012:126:2277-2279.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31307-2/fulltext
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:
- 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.
- Low-dose aspirin may be harmful in those who weigh less than 50 Kg. (including an increased risk of sudden death).
- Enteric coated or sustained release aspirin products may be less effective.
- Alternate day dosing may be less effective.
- 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.
- 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:
- Low-dose aspirin did not alter the rate of cancer in those who weighed 70 Kg or more.
- 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).
- High-dose aspirin seemed to have a similar impact on cancer rates as that seen with low-dose aspirin.
- 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.
- 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:
- Low-dose aspirin increases major bleeding up to a body weight of 90 Kg, above which bleeding risk disappears.
- 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. http://dx.di.org/10.1016/S0140-6736(18)31133-4
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
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.
- 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.
- 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.
- Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with warfarin against recurrent venous thromboembolism. NEJM 2000;342:1953-8.
- 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.
- 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.
- 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.
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.
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: www.acforumbootcamp.org.