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  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 = 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). 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 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  and ASPECT 2  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||
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|
*ASPECT 2: Aspirin +/- VKA INR 2-2.5 or VKA 3-4
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 , 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.
- 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).
- 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
- 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.
- Hurlen M, et al. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002; 347:969-974.
- 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.
- 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.
- 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.
- 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.
- 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, 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.
- 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.
- 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.
Henry I. Bussey, Pharm.D.
Qessential Research is a research company that has asked ClotCare to help make individuals aware of a survey research project that they are conducting. This is an industry-sponsored study, ClotCare does not know what company is sponsoring the study and ClotCare is neither supporting or recommending the study. ClotCare is simply acting as a conduit to help potentially interested patients to be aware of this study. The information below was provided by Qessential Research.
“Qessential Research is holding confidential interviews with individuals who have been diagnosed by a physician with blood clots in the leg, also known as Deep Vein Thrombosis. We are hoping to learn about your experience with this condition.
Who: Men and women who have been diagnosed by a physician with Deep Vein Thrombosis
What: Participate in a confidential interview to discuss your personal experience with DVT. The discussion will last about 60 minutes and you will receive $100 for your assistance.
When: Interviews will be held in June, at a time convenient for you.
If you would like to participate or would like more information, please call Deborah Booker at 1-800-932-4249 or via email at Deborah@QMMR.net.
As a professional firm in the medical industry, we understand privacy rules and do not give out any information about anyone involved in our studies. We do not ask for any information regarding patients’ personal medical situation nor are we providing any information about drugs, therapies, or any other promotional information.”
(with limited edits by Henry I. Bussey, Pharm.D.)
Editor’s Note #1: Charles J. Glueck, MD of the Jewish Hospital in Cincinnatti has shared with ClotCare his work on the relationship of testosterone supplementation and venous thrombosis and osteonecrosis (clotcare.org/testosterone_factor_v_clot_risk.aspx and clotcare.org/dvt_pe_testosterone_women.aspx ). He has provided us with an update on this topic. Dr. Glueck also offers his services at no cost to ClotCare users who have experienced blood clots while using a testosterone supplement. You may contact him at email@example.com or firstname.lastname@example.org
Venous thromboembolism (VTE) includes blood clots in the legs (known as deep vein thrombosis or DVT) and blood clots in the lungs (known as pulmonary embolism or PE). Whether testosterone supplementation therapy (TT) increases the risk of VTE, heart attack, and/or stroke remains at least somewhat controversial. Earlier work (cited above in the editor’s note #1) has suggested that TT, when administered to individuals with conditions that predispose them to clotting, does indeed carry a substantial risk of VTE. The information reviewed below provides further support for this position.
Martinez and colleagues recently examined the relationship of TT and VTE in a population-based case-control study of 9,215 patients with confirmed VTE (DVT and PE) compared to 909,530 age matched controls from a source population of more than 2.22 million men.1 Three testosterone exposure groups were identified: (1) current TT treatment (subdivided further by those with a duration
In our study of 67 men with VTE events while on TT, like Martinez and associates, we observed a peak VTE event rate at 3 months, with 60% of thrombotic events occurring within the first 8 months after starting TT.2, 3 The peak of VTE events around 3 months 1 and subsequent decline may reflect the early depletion of susceptible patients with familial or acquired thrombophilia-hypofibrinolysis4 where TT interacts with procoagulants to produce VTE. 3 Such “depletion” of susceptible patients from the group over time would leave a pro-coagulant-winnowed residual group with progressively fewer and fewer susceptible individuals over time. Such an effect would yield fewer and fewer VTE events over time. In other words, those individuals at risk of clotting with TT tend to have their VTE events early in the course of therapy and are removed from the pool of study patients so that the continued follow-up of the remaining patients may not show a significant risk of VTE. This effect may explain why cardiovascular events – but not VTE events – were increased with TT by injection in the study described in the editor’s note #2 below.5
Editor’s Note #2: TT may be administered by injection, topical gel, or topical patch. The injectable form is thought to provide higher peak levels of testosterone while the topical preparations provide lower but more sustained concentrations. To assess the safety of these formulations, Layton and colleagues performed a retrospective study of 544,115 TT users. Among this very large group of TT users, 37.4% received injections, 6.9% used the patch, and 55.8% used the gel formulation.5 It is important to note that there was not a non-TT control group. The risks (reported as hazard ratios and 95% confidence intervals – or CI) were higher for those receiving TT by injection. When compared to those receiving gel TT, the injectable group had hazard ratios of 1.26 (CI 1.18 – 1.35) for cardiovascular events (ie, heart attack, stroke, and angina), 1.16 (CI 1.13 – 1.19) for hospitalizations, and 1.34 (CI 1.15 – 1.56) for death. The hazard ratio for VTE, however, was not increased (0.92, CI 0.76 – 1.11). The event rates in the small portion of patients who used the patch, were virtually identical to the rates seen with gel use. Although the retrospective nature of this very large study weakens the findings, one might well conclude that the gel or patch may be safer forms of TT. It is important to note, however, that efficacy was not evaluated in this study and that one cannot draw any conclusions about the safety of these agents vs. no TT from this study.
- Martinez C, Suissa S, Rietbrock S, Katholing A, Freedman B, Cohen AT, et al. Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ. 2016; 355: i5968.
- Glueck CJ, Lee K, Prince M, Jetty V, Shah P, Wang P. Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant. J Investig Med High Impact Case Rep. 2016; 4(3): 2324709616661833.
- Glueck CJ, Prince M, Patel N, Patel J, Shah P, Mehta N, et al. Thrombophilia in 67 Patients With Thrombotic Events After Starting Testosterone Therapy. Clin Appl Thromb Hemost. 2016; 22(6): 548-53.
- Miettinen OS, Caro JJ. Principles of nonexperimental assessment of excess risk, with special reference to adverse drug reactions. J Clin Epidemiol. 1989; 42(4): 325-31.
- Layton JB, Meier CR, Sharpless JL, et al. Comparative Safety of Testosterone Dosage Forms. JAMA Intern Med. 2015:175(7):1187-96
Henry I. Bussey, Pharm.D.
If you have experienced a deep vein thrombosis (DVT) or pulmonary embolus (PE), a survey research company may be interested in talking with your in New York City (NYC). This in-person market research study is taking place in NYC on Tuesday, November 29, 2016. The compensation for those who qualify for the interview is $200 for a 90 minute interview. If interested, contact Carol Wager at email@example.com or call 732-662-4539.
Note: ClotCare is simply passing on information regarding this study. ClotCare is not affiliated with the study, has not reviewed or approved the survey, and we do not know which company is sponsoring the survey.
Below is a letter received from the Thrombosis Research Institute in London asking for clinicians involved in this area to help with a global survey.
Dear Dr. or Professor:
I am writing to request your participation in the Fundamental Research in Oncology and Thrombosis, Frontline2 survey.
The understanding of best practice for preventing and treating thrombosis in cancer patients has evolved significantly over the last decade, but variations in practice still persist. The aim of this research is to describe the evolution of clinical understanding in this area since the first FRONTLINE survey in 2001, and also to highlight variations in care, nationally and internationally.
Frontline2 is a global survey, designed by leaders in the field who as an expert steering committee provide global leadership for this important programme. It is funded by an unrestricted grant from Bayer Pharma AG. The survey will collate the views of oncologists, haematologists, surgeons, radiation oncologists and members of the palliative care team who are responsible for treating cancer-associated thrombosis. The work is sponsored and coordinated by the Thrombosis Research Institute (TRI) in London (www.TRI-LONDON.AC.UK).
Why you should take part
The value of this survey lies in achieving as large and as representative a sample of clinicians as possible to generate new insights into this important clinical problem, and to help resolve unanswered questions as well as potentially stimulating further research.
By giving a few minutes of your time to complete the questionnaire, you will provide crucial information to help meet these goals.
How you can contribute
Please complete the survey via our dedicated website frontline2.tri-London.ac.ukwhere you can also find more information about us and the study. The survey will also be available in multiple languages
As a thank you for your help in completing the survey, you can download from our website, an educational slide set prepared by the TRI. The goal of the slide series is to support the continued professional education in the field of venous thromboembolism and in particular cancer-associated thrombosis. In addition, all participants in the study will be granted first-hand access to the FRONTLINE 2 results once published.
I thank you in advance for your support and collaboration on this important piece of research.
Professor the Lord Kakkar
Chairman of the Steering Committee for
The Fundamental Research in Oncology and Thrombosis (Frontline2) study
THROMBOSIS RESEARCH INSTITUTE
Emmanuel Kaye Building
London SW3 6LR
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