Literature Review: NOACs vs. Warfarin

The following paper is a literature review examining the effects of novel oral anticoagulants (NOACs) versus warfarin in the reduction of stroke rates in patients with atrial fibrillation.

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Cox, D. (2017). For Patients with Atrial Fibrillation, Does the Use of Novel Oral Anticoagulants Reduce the Incidence of Stroke Compared with Warfarin? Nursejanx.

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Running head:  noacs versus warfarin 1

For Patients with Atrial Fibrillation, Does the Use of Novel Oral Anticoagulants Reduce the Incidence of Stroke Compared with Warfarin?

David H. Cox

Maryville University

NURS 601

July 8, 2017

For Patients with Atrial Fibrillation, Does the Use of Novel Oral Anticoagulants Reduce the Incidence of Stroke Compared with Warfarin?

Atrial fibrillation (AF) is the most prevalent heart arrhythmia on the planet, and studies have established that AF increases a person’s relative risk of suffering from a stroke (Chinitz, Castellano, Kovacic, & Fuster, 2012; Patel et al., 2011).  Vitamin K antagonist therapy (warfarin) has demonstrated the ability to reduce the incidence of stroke, but it suffers from several drawbacks such as the need for consistent laboratory monitoring, inadequate international normalized ratio (INR) control as demonstrated by time in therapeutic range (TTR), and increased rates of major bleeding events and mortality (Connolly et al., 2011).  This review will examine the literature in efforts to determine if the use of novel oral anticoagulants (NOACs) can reduce the incidence of stroke compared with warfarin while offering equal or better rates of major bleeding and mortality, effectively resolving many of the drawbacks of warfarin therapy.

Overview

Background

According to Chinitz et al. (2012), AF currently affects 1-2% of the world’s population and is considered the most common heart arrhythmia.  Worse, is that AF rates are expected to double within the next 50 years (Chinitz et al., 2012).  Stroke has consistently ranked in the top five leading causes of death in the United States, and AF has been shown to increase a patient’s risk of having a stroke by up to 400% (Chinitz et al., 2012; Murphy, Kochanek, Xu, & Arias, 2015).

Until the recent development of NOACs, warfarin therapy has been used for stroke prophylaxis in AF patients.  Multiple studies have demonstrated the efficacy of warfarin for this purpose, making it the recommended therapy for stroke prevention in this population (Connolly et al., 2009, 2011).  However, there are several documented issues associated with warfarin therapy including an increased risk of hemorrhage, complicating food and drug interactions, and the requirement for frequent lab testing to ensure that the drug levels are therapeutic to name a few (Connolly et al., 2009; Patel et al., 2011).  According to Connolly et al. (2009), these drawbacks can lead to disuse, discontinuation, and inadequate anticoagulation therapy.

Recently, the medical community has witnessed the development and approval of several NOACs as a viable alternative to warfarin therapy, including dabigatran, apixaban, rivaroxaban, and edoxaban.  This literature review will compare various aspects of NOAC therapy with warfarin therapy to determine if NOACs are equally efficacious, safer, and have fewer drawbacks when compared with warfarin.

Search History

A PICO question was developed to guide this literature review, and is as follows:  For patients with AF, does the use of NOACs reduce the incidence of stroke compared with warfarin?  The population is patients with AF, the intervention is the use of NOACs, the comparison is warfarin, and the primary outcome is the incidence of stroke.

Using Maryville University’s online library, an advanced search was performed across all major databases by combining the searchable fields “atrial fibrillation,” “coumadin or warfarin,” “stroke or cerebrovascular accident or cva,” and “noac or doac or apixaban or dabigatran or rivaroxaban.”  The search mode was set to “find all my search terms,” and the results were limited by including “full text,” “available in library collection,” published date between 2011-2017, and in the English language.  A subsequent search was performed with the notable change of a published date limitation between 2005-2017 to include any additional pertinent studies.  This exact same search was also performed specifically on the CINAHL database through the Maryville University library with the noted additional limit of “research article.”

Personal Interest

Nurses working in an acute care hospital setting will frequently witnesses patients admitted for a stroke.  This sudden and often life-threatening debilitation is a difficult and challenging time for both patients and their loved ones.  If there is a better way of preventing this hardship, then it is the duty of healthcare professionals to provide it.  Future nurse practitioners will likely work with an aging population experiencing rising rates of AF.  With the continued development and knowledge of new and improved therapies such as NOACs, a noble goal for healthcare providers is to strive to help contribute to a decline in stroke rates.

Synthesis of the Evidence

Drawbacks of Warfarin Therapy

Inadequate TTR decreases the efficacy of warfarin treatment.  One of the main disadvantages of warfarin therapy is that patients must receive frequent laboratory testing to ensure that warfarin levels are within a therapeutic window.  This window is measured by an INR value, and time spent with an ideal INR is considered TTR.  

Dlott et al. (2014) performed a long-term observational study of AF patients taking warfarin to determine an average representative TTR in this population.  The authors claim that this was the largest recent study of anticoagulation rates to date (2014), and sampled a total of 138,319 patients.  According to Dlott et al., a TTR threshold of 58-65% is necessary for warfarin therapy to be effective, however, the average TTR in the Dlott et al. study was found to be 53.7% which is well below the previously established parameters.  The authors noted that these results were lower than observed results from other recent studies, but nevertheless, this study demonstrated inadequate anticoagulation therapy for nearly half of AF patients taking warfarin (Dlott et al., 2014).

In a study examining the effects of Apixaban compared to aspirin for anticoagulation, Connolly et al. (2011) stated that a meta-analysis of average TTR for patients in the United States was about 55%.  Because of this alone, the authors concluded that warfarin therapy was unsuitable for about a third of patients that are considered for it.  In addition, the authors found that similar percentages of patients would outright refuse warfarin therapy due to the many inconveniences and difficulties associated with its use (Connolly et al., 2011).

Multiple landmark studies included in this review have compared various NOACs to warfarin control groups, and all but one demonstrated adequate TTR averages for patients taking warfarin.  A study comparing Dabigatran to warfarin found that the average TTR across all patients taking warfarin was about 64% (Connolly et al., 2009).  In a study comparing Apixaban to warfarin, the average TTR across all patients taking warfarin was about 62% (Granger et al., 2011).  Another study comparing Edoxaban to a warfarin control group had the highest average TTR of 68.4% (Giugliano et al., 2013).  The lowest average TTR was found in a study comparing Rivaroxaban to warfarin.  In this study, the average TTR across all patients taking warfarin was only about 55% (Patel et al., 2011).  This was the lowest TTR reported in all the studies included in this review and falls below what Dlott et al. claim is necessary for warfarin therapy to be effective.

Increased risk of stroke after initiating warfarin therapy.  Azoulay, Dell’Aniello, Simon, Renoux, and Suissa (2014) performed a cohort study of 70,766 patients with AF taking warfarin.  Azoulay et al. found that there was a significant increase of up to 71% for stroke rates within the 30 days of starting warfarin therapy.  Tung et al. (2015) found similar results when they led a population-based observational study of 148,446 patients with AF that found an increased rate of stroke within the first 30 days of starting warfarin therapy.  According to Tung et al., it is unlikely that this initial spike in stroke rates is simply due to a recent diagnosis of AF because the patients in the study were bridged to warfarin therapy with heparin and other anticoagulants.  According to Tung et al., this suggests a possible hypercoagulable state that could be related to warfarin therapy, and while the authors could not prove that warfarin was causing this increase in stroke incidence (due to the nature of their observational study), they recommended that future research should be conducted for a better understanding of this unsettling phenomenon.

NOACs are Superior to Warfarin in the Reduction of Stroke Incidence

One of the primary goals of this literature review is to determine if NOACs are equivalent or even superior to warfarin at reducing the incidence of stroke in patients with AF.  In the research phase, multiple landmark trials that compared warfarin to various NOACs were discovered.

Dabigatran study.  The first landmark study included in this review was led by Connolly et al. (2009) and sought to examine the effects of two different doses of Dabigatran on stroke incidence in AF patients compared with warfarin.  This study was a well-designed, long-term, controlled, blind, randomized trial of patients with AF.  According to Connolly et al., this quantitative research study required a sample of 15,000 patients to allow for the effective measurement of non-inferiority within both test groups of Dabigatran.  With a total of 18,113 patients, the sampling numbers were beyond sufficient.  The sources of funding for this research were clearly stated to avoid potential bias, and the authors mentioned that the study was approved by all necessary ethics committees (Connolly et al., 2009).

In this study, Connolly et al. concluded that stroke rates were 1.53% per year in the Dabigatran 110mg test group, 1.11% per year in the Dabigatran 150mg test group, and 1.67% per year in the warfarin control group.  At both doses, Dabigatran exhibited a reduction of stroke rates, but the 150mg dose demonstrated the larger reduction of relative risk of stroke by 34% when compared with warfarin.  The 110mg dose, although less impressive, still demonstrated a reduction of relative risk of stroke by 9% when compared with warfarin.  Both doses were considered to be noninferior to warfarin therapy (Connolly et al., 2009).

Apixaban study.  In a second landmark study on NOACs, Granger et al. (2011) examined the effects of Apixaban on stroke incidence in AF patients compared with warfarin.  This was a long-term, controlled, blind randomized trial of patients with AF.  According to Granger et al., this quantitative research study required a sample of 18,000 patients to allow for the effective measurement of non-inferiority and relative risk of Apixaban.  With a total of 18,201 patients, the sampling numbers were beyond sufficient.  The authors mention that this study was led by representatives from the drug companies that sponsored the study which could suggest potential bias, although it would appear to be a well-designed and executed study, and was approved by all necessary ethics committees (Granger et al., 2011).

Granger et al. concluded that in AF patients assigned to the Apixaban test group, the rate of stroke was 1.27% per year compared to 1.6% per year for the warfarin control group.  Using these results, Apixaban was calculated to have reduced the relative risk of stroke by roughly 21% when compared with warfarin and was considered to be noninferior to warfarin therapy (Granger et al., 2011).

Rivaroxaban study.  In a third landmark study on NOACs, Patel et al. (2011) examined the effects of Rivaroxaban on stroke incidence in AF patients compared with warfarin.  This study was a long-term, controlled, double-blind, double-dummy, randomized trial of patients with AF.  According to Patel et al., this quantitative research study required a sample of 14,000 patients to allow for the effective measurement of the efficacy of Rivaroxaban.  With a total of 14,264 patients, the sampling numbers were beyond sufficient.  Patel et al. clearly stated all research sponsors, and note that the study was approved by all necessary ethics committees (Patel et al., 2011).

One notable concern is that the average TTR of the warfarin control group reported in this study is the lowest of all studies included in this literature review (Patel et al., 2011).  According to Dlott et al. (2014), an adequate TTR for warfarin to be effective is 58-65%.  If the average TTR in the Rivaroxaban study was below the required threshold at only 55%, then the findings of this study may not accurately represent an honest and fair comparison between Rivaroxaban and warfarin, as the anticoagulation within the warfarin control group was likely ineffective.  It would be beneficial for future research to re-examine Rivaroxaban compared to a warfarin control group with an adequate average TTR to see if the results remain the same.

Despite this concern, Patel et al. (2011) found that in patients taking Rivaroxaban, the rate of stroke was 1.7% per year compared to 2.2% per year for warfarin.  Using these results, Rivaroxaban was calculated to have reduced the relative risk of stroke by roughly 23% when compared with warfarin and was considered to be noninferior to warfarin therapy.  The authors also stated that despite the inadequate TTR reported in the warfarin control group, that Rivaroxaban still outperformed warfarin at every metric, just to a lesser degree when the INR was better controlled (Patel et al., 2011).

Edoxaban study.  Finally, Giugliano et al. (2013) studied the effects of two different doses of Edoxaban on stroke incidence in AF patients compared with warfarin.  This was a controlled, three group, double-blind, double-dummy, randomized trial of patients with AF.  The study included 21,105 patients, but Giugliano et al. did not state a required sample number for this quantitative research study to allow for the effective measurement of the efficacy of Edoxaban.  Nevertheless, the authors stated their confidence in the results of this study (Giugliano et al., 2013).

Giugliano et al. concluded that stroke rates were 1.18% per year in the Edoxaban 60mg test group, 1.61% per year in the Edoxaban 30mg test group, and 1.50% per year in the warfarin control group.  According to these results, Edoxaban at the higher 60mg dose was calculated to have reduced the relative risk of stroke by roughly 22% when compared to warfarin.  However, in the lower 30mg dose of Edoxaban, the relative risk of stroke was actually higher than in the warfarin control group by about 7%.  Regardless of this slight increase, Giugliano et al. stated that both doses of Edoxaban were considered to be noninferior to warfarin therapy, but that they recommended the higher 60mg dose (Giugliano et al., 2013).

All the four NOACs included in this review demonstrated an improvement in stroke rates when compared with warfarin.  Three of the four studies had a warfarin control group with an adequate average TTR, which would indicate that warfarin was functioning properly during these comparison trials.  This should further increase the confidence in this evidence.

NOACs Decrease Bleeding Events and Mortality Compared with Warfarin

Another theme of this literature review relates to major bleeding events and mortality rates.  Similar to the previous section regarding stroke rates, when comparing different NOACs with warfarin, the NOACs often demonstrated non-inferiority and even superiority to warfarin in most situations regarding these variables.

 Dabigatran study.  In the landmark study comparing Dabigatran to warfarin, Connolly et al. (2009) examined the rates for both major bleeding and mortality.  In the warfarin control group, the authors found that the rate of major bleeding was 3.36% per year, and the mortality rate was 4.13% per year.  In the Dabigatran 110mg dose test group, the authors stated that the rate of major bleeding was 2.71% per year, and the mortality rate was 3.75% per year.  Finally, in the Dabigatran 150mg dose test group, the authors concluded that the rate of major bleeding was 3.11% per year, and the mortality rate was 3.64% per year.  According to these results, both doses of Dabigatran exhibited decreased rates of major bleeding and mortality when compared with warfarin.  The lower Dabigatran dose of 110mg was associated with the lowest bleeding rate, while the higher 150mg dose was associated with the lowest mortality rate (Connolly et al., 2009).

Apixaban study.  In the landmark study comparing Apixaban to warfarin, Granger et al. (2011) examined the rates for both major bleeding and mortality.  In the warfarin control group, the authors found that the rate of major bleeding was 3.09% per year, and the mortality rate was 3.94% per year.  In the Apixaban test group, the authors stated that the rate of major bleeding was 2.13% per year, and the mortality rate was 3.52% per year.  According to these results, Apixaban demonstrated a reduction in bleeding rates of about 31%, and reduction in mortality rates of about 11% (Granger et al., 2011).

Rivaroxaban study.  In the landmark study comparing Rivaroxaban to warfarin, Patel et al. (2011) examined the rates for both major bleeding and mortality.  Although Rivaroxaban was superior to warfarin in the reduction of stroke incidence, the NOAC did not demonstrate additional benefits for the reduction of bleeding events or overall mortality when compared with the warfarin test group (Patel et al., 2011).

Of note, this study had issues with the average TTR in the warfarin control group.  Perhaps if the TTR was adequate, as it was in the other studies, warfarin could have possibly caused more bleeding events by thinning the blood further.  This would have hypothetically influenced the final results of this study.  Further research should be conducted comparing rivaroxaban to a warfarin control group with an adequate average TTR to see if the results remain the same.

Edoxaban study.  In the study comparing edoxaban to warfarin, Giugliano et al. (2013) also examined the rates of both major bleeding and mortality.  In the warfarin control group, the authors found that the rate of major bleeding was 3.43% per year, and the mortality rate was 4.43% per year.  In the edoxaban 30mg dose test group, the authors stated that the rate of major bleeding was 1.61% per year, and the mortality rate was 4.23% per year.  Finally, in the Edoxaban 60mg dose test group, the authors concluded that the rate of major bleeding was 2.75% per year, and the mortality rate was 3.85% per year.  According to these figures, the authors concluded that both doses of Edoxaban demonstrated decreased rates of major bleeding and mortality when compared with warfarin.  Similar to the Dabigatran study, the higher Edoxaban 60mg dose exhibited the most substantial reduction in mortality rates, while the lower dose of 30mg exhibited the most pronounced reduction in major bleeding rates (Giugliano et al., 2013).

Gaps in the Evidence

Unlike NOACs, warfarin needs to be dosed continuously to maintain a therapeutic INR to be effective.  TTR differed in all studies included in this literature review.  According to Dlott et al. (2014), an adequate TTR for warfarin efficacy is between 58-65%.  The highest TTR reported in all included studies was 68.4% and the lowest was 55%.  Had the TTR of all studies been consistent, the results may have differed.  However, inadequate and variating TTR is a known issue with warfarin therapy and is representative of the greater population taking this medication.

NOACs are new drugs compared to warfarin.  Although several impressive landmark studies have been conducted comparing NOACs to warfarin, future research should aim to improve where existing research is limited.  If warfarin control groups can achieve consistent and adequate average TTRs, then the comparison results may be more valid.

There were also several studies that found a spike in stroke incidence within the first 30 days of starting warfarin therapy.  Tung et al. (2014) believed that in addition to being correlated with this increase, that warfarin cannot be ruled out as a causing factor in this phenomenon.  They suggested that future research should focus on any potential hypercoagulable state that warfarin therapy may create during its initiation.

Comparison to Practice

In an acute care hospital setting, this author can attest to the use of NOACs for anticoagulation in AF patients as well as other patients requiring anticoagulation.  However, the most common anticoagulants still appear to be older therapies such as heparin and warfarin.  Perhaps as research continues to advance and NOACs become more familiar, healthcare workers will see a rise in their use and popularity.

Significance to Nursing

Adequate anticoagulation therapy is paramount for the AF patient to reduce the risk of stroke and decrease mortality.  As part of the interdisciplinary healthcare team, nursing must strive to ensure that AF patients are offered the best prophylactic medication therapies that are available.  If the evidence demonstrates that NOACs are superior to warfarin in the prevention of stroke, then the best practice would dictate that they should be recommended unless contraindicated.  Due to the novelty of NOACs, many patients and perhaps even some primary care providers may not be aware of alternative therapies to warfarin.  As patient educators, nursing can inform AF patients on the various options available to help them better care for themselves.

Conclusion

Warfarin treatment is effective in the reduction of stroke incidence in AF patients.  However, in addition to various inconveniences, studies have demonstrated that patients on warfarin therapy are likely to suffer from inadequacies in TTR which can render the therapy dangerous and ineffective.  Multiple studies have concluded that NOACs are noninferior and even superior to warfarin for the prevention of stroke in AF patients.  In addition, NOACs were found to be safer than warfarin with reduced rates of both major bleeding events and mortality.  Hopefully, further research will offer more information on these newer anticoagulation therapies.  For these reasons, NOACs should be regularly considered as a first-line treatment option for AF patients unless otherwise contraindicated.

References

Azoulay, L., Dell’Aniello, S., Simon, T. A., Renoux, C., & Suissa, S. (2014). Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes. European Heart Journal, 35(28), 1881–1887. Retrieved from http://dx.doi.org/10.1093/eurheartj/eht499

Chinitz, J. S., Castellano, J. M., Kovacic, J. C., & Fuster, V. (2012). Atrial fibrillation, stroke, and quality of life. Annals of the New York Academy of Sciences, 1254, 140–150. https://doi.org/10.1111/j.1749-6632.2012.06494.x

Connolly, S. J., Eikelboom, J., Joyner, C., Diener, H.-C., Hart, R., Golitsyn, S., … Yusuf, S. (2011). Apixaban in patients with atrial fibrillation. New England Journal of Medicine, 364(9), 806–817. https://doi.org/10.1056/NEJMoa1007432

Connolly, S. J., Ezekowitz, M. D., Yusuf, S., Eikelboom, J., Oldgren, J., Parekh, A., … Wallentin, L. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 361(12), 1139–1151. https://doi.org/10.1056/NEJMoa0905561

Dlott, J. S., George, R. A., Huang, X., Odeh, M., Kaufman, H. W., Ansell, J., & Hylek, E. M. (2014). National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation. Circulation, 129(13), 1407–1414. Retrieved from http://circ.ahajournals.org/content/129/13/1407.abstract

Giugliano, R. P., Ruff, C. T., Braunwald, E., Murphy, S. A., Wiviott, S. D., Halperin, J. L., … Antman, E. M. (2013). Edoxaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 369(22), 2093–2104. https://doi.org/10.1056/NEJMoa1310907

Granger, C. B., Alexander, J. H., McMurray, J. J. V, Lopes, R. D., Hylek, E. M., Hanna, M., … Wallentin, L. (2011). Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine, 365(11), 981–992. https://doi.org/10.1056/NEJMoa1107039

Murphy, S. L., Kochanek, K. D., Xu, J., & Arias, E. (2015). Mortality in the United States, 2014. Retrieved from https://www.cdc.gov/nchs/data/databriefs/db229.pdf

Patel, M. R., Mahaffey, K. W., Garg, J., Pan, G., Singer, D. E., Hacke, W., … Califf, R. M. (2011). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine, 365(10), 883–891. https://doi.org/10.1056/NEJMoa1009638

Tung, J. M., Mamdani, M. M., Juurlink, D. N., Paterson, J. M., Kapral, M. K., & Gomes, T. (2015). Rates of ischemic stroke during warfarin treatment for atrial fibrillation. Stroke, 46(4), 1120–1122. Retrieved from http://stroke.ahajournals.org/content/46/4/1120.abstract

 

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