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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: www.acforumbootcamp.org.

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 Medscape.com 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 (www.medscape.com/viewarticle/888355), 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 ClotCare.org 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 http://journal.chestnet.org/article/S0012-3692(12)60126-3/pdf ).  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 http://www.clotcare.com/vtekneearthoscopy.aspx  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 (https://www.ncbi.nlm.nih.gov/pubmed/24190733 and https://www.ncbi.nlm.nih.gov/pubmed/24581264).  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

https://www.ncbi.nlm.nih.gov/pubmed/26630467).  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.

Today (Oct. 13, 2017) is World Thrombosis Day…. check it out!

Henry I. Bussey, Pharm.D.,

Join thousands of partners, survivors, supporters, and many others around the world today to recognize and celebrate World Thrombosis Day (WTD) 2017.

More than 1,000 campaign partners in more than 85 countries have organized thousands of events and activities that are taking place today. In addition, our global community is spreading the word through social media and other digital activities to educate and inspire others.

ClotCare.org, a participating partner, appreciates the enthusiasm, time, support, and creativity as we stand together in a united effort to raise awareness about potentially deadly blood clots. With 1 in 4 people worldwide dying of conditions related to thrombosis, there is no better time than right now to take action.  In the U.S. blood clots in the venous system [venous thrombembolism or “VTE”] kill more people that HIV/AIDS, breast cancer, and auto accidents COMBINED!!  And that does not include the clots that cause heart attacks and strokes.

Let’s #KnowThrombosis and #KeepLifeFlowing.

[Figure from WTD website… for more information check out http://www.worldthrombosisday.org/]

Rivaroxaban or Warfarin in Stable Coronary Artery Disease – Should the COMPASS Study Lead Us Back to the Future?

Henry I. Bussey, Pharm.D.


The recently published (online) COMPASS trial [1] of rivaroxaban (brand name Xarelto) with or without aspirin in patients with stable coronary artery disease (CAD) and peripheral vascular disease has been touted as a practice-changing break-through study that supports adding rivaroxaban to the therapy of such patients.  Approximately 90% of enrolled patients had CAD. Four key questions to be addressed are listed below.  The COMPASS trial was a double blind, double dummy randomized trial that compared the three therapies: aspirin alone, aspirin + rivaroxaban 2.5 mg twice a day, and rivaroxaban 5 mg twice a day (without aspirin).  Because the 5 mg rivaroxaban group did not show clear benefit and had a higher bleeding rate than the other 2 arms, this discussion will focus only on the aspirin alone and the aspirin + 2.5 mg rivaroxaban twice a day groups.

  • Exactly how beneficial is the addition of rivaroxaban to aspirin?
    •  Answer: One stroke, heart attack, or cardiovascular death prevented for every 154 patients treated for a year.
  • What is the risk of adding rivaroxaban?
    • Answer: One additional major hemorrhage for every 166 patients treated for a year.
  • Why was a vitamin K antagonist (VKA) such as warfarin not tested in this trial ?
    • Perhaps the safety and efficacy of warfarin in coronary artery disease has been forgotten?
    • The pharmaceutical industry lacks interest in funding research with warfarin.
    • What if warfarin outcomes were superior to rivaroxaban?
  • What might be the impact of warfarin if well managed with frequent INR self-testing?
    • Projected to double the safety and efficacy of warfarin reported in previous studies (based on data from atrial fibrillation data bases).
    • Might be significantly more effective and safe than rivaroxaban.
    • Reduced time, hassle, and expense of warfarin management.

General Considerations: The COMPASS study has 3 “red flag” issues that raise concerns from a study design and execution perspective:

  • Size of study: As a general rule, the smaller the anticipated impact of a given therapy, the larger the study population will need to be in order to find a statistically significant difference.  For that reason, I am usually skeptical of the clinical benefit of any study that requires more than 10,000 patients to show a statistically significant difference. The COMPASS study enrolled 27,395 patients.
  • Composite endpoint:  Combining several clinical events into a single primary outcome (such as stroke, heart attack, and cardiovascular death) can be another indicator of trying to make a small clinical difference be statistically significant; but in this case, this is the same 3-component composite that has been used in previous post CAD studies and each component is very important.
  • Geographic and ethnic considerations:  Individuals living in different parts of the world, those living in different cultures, and those with different genetic predispositions may have different outcomes of treatment.  Therefore, one should always consider whether the patients studied are comparable to one’s own patients.  In COMPASS, patients were enrolled from 5 geographic regions around the world and each region showed a trend toward benefit of rivaroxaban + aspirin.  However, only 14% of patients came from North America sites and the impact of rivaroxaban was not statistically in this sub- of group of almost 4,000 patients.  The impact of rivaroxaban was statistically significant in 2 of the 5 regions (Eastern Europe and Asia/Pacific) which together enrolled almost 9,000 patients (32% of all patients).  One has to question whether the impact of rivaroxaban + aspirin would have been statistically significant without including the patients from Eastern Europe and Asia/Pacific area who appeared to benefit more than did those from other regions.

Exactly how beneficial was rivaroxaban?  COMPASS compared rivaroxaban 2.5 mg twice a day + 100 mg of aspirin to rivaroxaban 5 mg twice a day (and no aspirin) to aspirin 100 mg daily.  The primary outcome of stroke + heart attack + cardiovascular death was reduced by 24% in the group that got 2.5 mg of rivaroxaban + aspirin twice a day!!  In the group getting 5 mg of rivaroxaban twice a day (without aspirin), the primary outcome was reduced by 9%, but that difference was not statistically significant even though each group had more than 9,000 patients. But what does the 24% reduction with the 2.5 mg dose actually mean?  The event rates in the two groups were 5.4% with aspirin alone vs. 4.1% with rivaroxaban 2.5 mg twice a day + aspirin over a mean follow-up of 23 months.  Those event rates (over 23 months) would equal annualized event rates of approximately 2.7% with aspirin alone vs. 2.05% with rivaroxaban + aspirin; a difference of 0.65% per year [see Table 1].  That means that one would need to treat 154 patients for a year in order to prevent one patient from experiencing one of the composite events.   While preventing one stroke, heart attack, or cardiovascular death per year is certainly a valuable goal, one must consider the risks of such therapy.  The cost of the additional therapy for all 154 patients should also be factored in but the cost will not be considered here because, as far as I know, the 2.5 mg tablet is not yet available.

What is the risk of adding rivaroxaban?

The major risk of adding rivaroxaban to aspirin is bleeding.  The rate of major bleeding with aspirin was 1.9% while the rate of major bleeding with 2.5 mg of rivaroxaban + aspirin was 3.1%.  Although that is a 63% relative increase, the absolute annualized difference is only 0.6% [see Table 1].  The number needed to treat of 154 vs the number needed to harm of 166 indicate that approximately 9 additional major hemorrhages would occur for every 10 composite events prevented.

Table 1. Annualized Event Rates per 100 patients from the COMPASS Trial


Aspirin + R 2.5 mg Diff. NNT


Primary Outcome


2.05 0.65


Major hemorrhage


1.55 0.60


Primary outcome = composite of stroke, heart attack, and cardiovascular death.  NNT = number of individuals who would need to be treated for a year to prevent one event, NNH = number of individuals who would need to be treated for a year in order to cause one additional major hemorrhage.

Why was a VKA such as warfarin not included?  For the last several years, the focus of clinical literature (and pharmaceutical advertising) in the area of anticoagulation has been on the newer DOACs (Direct-acting Oral AntiCoagulants) such as rivaroxaban.  But slightly earlier data has documented the merits of warfarin alone or in combination with aspirin in patients with a recent acute CAD event.  Anand and Yusuf provided a nice review of this issue in 2003 and pointed out the importance of achieving an adequate International Normalized Ratio ( INR).[2]  Studies that targeted an INR less than 2.0 did not show benefit with VKA therapy, but benefit was seen with an INR target of 2 to 2.5 + aspirin or an INR of approximately 3 to 4 without aspirin.  The COMPASS trial, however, enrolled patients with stable CAD and I am not familiar with any recent studies that evaluated warfarin in similar patients.  The COMPASS trial was based on the results of the ATLAS trial[3] which was conducted in patients with a recent acute CAD event, so the following discussion will compare the ATLAS results with a couple of example studies of warfarin +/- aspirin in patients recent acute CAD events.  The ATLAS trial randomized 15,526 patients to rivaroxaban 2.5 mg twice a day, rivaroxaban 5 mg twice a day, or placebo; all patients received aspirin and/or other antiplatelet therapy.  The primary endpoint was stroke, heart attack, or cardiovascular death.  The WARIS II [4] and ASPECT 2 [5] trials were somewhat similar studies that randomized patients with acute CAD events to aspirin alone, aspirin + warfarin with a target INR of 2 to 2.5, or warfarin alone at an INR of approximately 3 to 4.  Based on NNT and NNH, it would appear that the warfarin regimens in WARS II and ASPECT 2 were at least comparable in safety and efficacy to rivaroxaban in the ATLAS trial. [see Table 2].

Table 2: Outcomes in Acute CAD with Rivaroxaban or Warfarin +/- Aspirin

ATLAS: Aspirin +/- Rive 2.5 BID or 5 mg BID (n = 15,526)


Aspirin + R 2.5 mg  Aspirin + R 5 mg Diff. v. 2.5/5 R NNT 2.5/5


Primary Outcome


9.1 8.8 1.6/1.9 63/53
Major Hem.


2.1 2.1 1.5


WARIS II: Aspirin +/- VKA INR 2-2.5 or VKA 3-4


Aspirin+ VKA INR 2-2.5 VKA 3 – 4 Diff vs INR 2-2.5/3-4 NNT at INR 2-2.5/3-4
Primary Outcome


3.67 4.21 1.49/0.95


Major Hem.


0.62 0.62 0.45


*ASPECT 2: Aspirin +/- VKA INR 2-2.5 or VKA 3-4

Primary Outcome

9.2 4.8 5.2 4.4/4.0 23/25
Major Hem.


2.0 1.0 1/0


CAD = coronary artery disease (defined differently in the different studies), VKA = vitamin K antagonist (such as warfarin, brand name Coumadin). R = rivaroxaban, Hem = hemorrhage, INR = International Normalized Ratio which is the blood test used to measure the intensity of the anticoagulant effect of VKAs. NNT = the estimated number of individuals who would need to be treated for one year to prevent one primary event.  NNH = the estimated number of individuals who would need to be treated for one year in order to cause one additional major hemorrhage.

*Median (rather than mean) length of follow-up of 12 months was reported in the ASPECT study but it was presumed that the mean follow-up was also 12 months.

What might be the impact of warfarin if well managed with frequent INR self-testing?  There have been two major problems with warfarin management – (1) the difficulty of keeping the INR in the optimal range and (2) the time, hassle and costs of trying to achieve optimal INR control.  Several small studies [6 – 13] have demonstrated that these two obstacles to warfarin use can be greatly reduced by combining INR self-testing with online automated management.  In our own small study of self-testing and online management [11], we were able to maintain the INR in range more than 80% of the time for a group of patients who previously had a mean time in range of 56%.  Such improved INR control was achieved (and maintained) with a minimal amount of time and effort on the part of the clinician and the patient.  Two large data sets in patients with atrial fibrillation have defined the relationship between improved INR time in range and major clinical events and mortality.[14, 15]  Based on the relationship defined in those two reports, the improved INR control with INR self-testing and online management is projected to reduce major clinical events by more than 80% and mortality by more than 40% [see Figure].  If patients with an acute CAD event can derive benefit similar to that projected for better INR control in patients with atrial fibrillation, then the VKA-related event rates in Table 2 would be reduced by more than 50% making well-managed VKA therapy superior to rivaroxaban.


Conclusion:  The addition of rivaroxaban 2.5 mg twice a day plus low dose aspirin can reduce the incidence of the composite endpoint of stroke, heart attack, and death in patients with stable CAD.  But this benefit is small (less than 1%/yr.) and off-set by a similar increased rate of major hemorrhage (also less than 1%/yr.).  How VKA (warfarin) therapy (with or without aspirin) may alter outcomes in stable CAD patients is not known.  But data from different studies (with the acknowledged hazards of cross-study comparisons) in patients with a recent acute CAD event suggest that warfarin alone or warfarin plus low dose aspirin may be at least as safe and effective as rivaroxaban plus antiplatelet therapy.  INR self-testing and online management, which has the potential to transform INR control and VKA management efficiency, may provide an avenue to improve outcomes with warfarin therapy beyond that which can be achieved with rivaroxaban and other DOACs.  There is a critical need to compare such optimal management of warfarin to the DOACs in patients with stable CAD, those with a recent acute CAD event, atrial fibrillation, and other indications.


  1. Eikelboom JW, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017 DOI: 10.1056/NEJMoa1709118    (http://dx.doi.org/10.1056/NEJMoa1709118).
  2. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003; 41:62S-69S. DOI: 10.1016/S0735-1097(02)02776-6
  3. Mega JL, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366:9-19.  DOI: 10.1056/NEJMoa1112277.
  4. Hurlen M, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002; 347:969-974.
  5. Van Es RF, et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002; 360:109-113.
  6. O’Shea SI, et al. Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation. J Thromb Thrombolysis 2008; 26(1): 14-21.
  7. 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.
  8. Ferrando F,  Mira Y, Contreras MT, et al. Implementation of SintromacWeb(R), a new internet-based tool for oral anticoagulation therapy telecontrol: Study on system consistency and patient satisfaction. Thromb Haemost 2010; 103:1091–1101.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. Harper P, et al. Evaluation of a community pharmacy anticoagulation management service utilizing point-of-care testing and online computerized decision support (Abstract ATT07). J Thromb Haemostas 2013; 11(S3):11-12.
  14. Gallagher AM, et al. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011; 106:968-977. doi: 10.1160/TH11-05-0353.
  15. Wan Y, 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. Doe: 10.1161/CIRCOUTCOMES.108.796185.