Ronelle E. Stevens, PharmD RPh, CACP

Over the past year, I’ve written about the cumbersome, often complex, and potentially dangerous nature of anticoagulant medications. With the New Year approaching, I propose that we resolve to decrease some of the difficulty by welcoming patients and technology into the patient counseling dialogue.

At the end of health care is patient care. While patients have been drivers for improvements in the health care “system”—in practice, quality, and delivery&mdash;it wasn’t until recently that we considered placing patients at the center of their own care. The Institute of Medicine’s reports “To Err Is Human: Building a Safer Health System,” “Crossing the Quality Chasm,” and most recently “Population Health Implications of the Affordable Care Act” have revealed a paradigm shift, and the recognition that patient-centered care and interoperability of health systems may lead to the transparency necessary to achieve meaningful and value-based care.

In 2009, the Health Information Technology for Economic and Clinical Health Act (HITECH) was enacted to promote and expand the adoption of health information technology.

 This meant improved health information exchange and thus better health care quality, safety, and efficiency. It also laid the groundwork for patients to become more proactive in their care via online patient portals and personal health records (PHRs), whereby patients have the opportunity to record and maintain information related to their health and to communicate with their primary caregivers and/or care team.

Technology is only as good as what you put into it—that is, garbage in begets garbage out. Eighty percent of medical errors began with miscommunication, missing or incorrect information about patients, or lack of access to patient records. There is certainly room for improvement.

 In alignment with preventing adverse drug events, patient-assisted medication reconciliation via patient portals and PHR responsibilities may be a start.

According to H. Edward Hanway, chairman and chief executive officer, CIGNA Corporation, “Individuals can and will make higher-quality health care decisions when given the education, motivation, and opportunity to do so ... personal responsibility and accountability, coupled with strong health advocacy and readily accessible cost and quality information, can make all the difference in reducing health care costs and improving quality of care.”

So what does this have to do with patient counseling? Patient counseling has become a bit trickier these days. With more Google searches for health information than doctor’s visits, it is difficult to be the primary source for appropriate disease management and medication adherence.

 Some health care providers view this as defiance since they want to be the primary source of consultation, while patients view this as research and patient engagement.

I recently had the good fortune of listening to the patient-centered perspective of Dave deBronkart, aka “e-Patient Dave.” In 2009, 

 magazine recognized him as one of the 20 most influential people who make health care better. He noted that patients are to be equipped, engaged, empowered, and enabled to participate in their care. He issued a challenge to rebalance the patient—physician dynamic in light of technologic resources and access to care via the new information ecosystem. “It’s perverse to keep people in the dark and call them ignorant,” he said.

This works both ways, for patients and clinicians, alike. In my experience, communication is a 2-way street and patients don’t require being spoken to, but spoken with—in an engaging manner that captures their daily routines, eating habits, and other potential barriers to adherence. This is especially true for education surrounding potentially complex and dangerous medications, including warfarin.

A decreased burden on an already overwhelmed health care “system” begins and ends with the patient. Participatory medicine via technology is the future state-of-the-art. We have more tools and resources now than ever, and because of the Web, people can connect to information quickly, so we must reevaluate our methods of patient engagement and counseling. Technology and telehealth provide the platform to enforce patient education and more accessible health care. We ought to view these tools as segues for further advancement of health care, and not as hindrances. As e-Patient Dave says, “When a patient wants to help, give them a shovel.”

Dr. Stevens is an advanced practice anticoagulation pharmacist for the Partners Healthcare System and an adjunct clinical assistant professor of pharmacy at Northeastern University’s BouveÌ College of Health Sciences in Boston, MA. This column’s information is based on current studies but may be updated without notice with newer studies or with different populations.

		Leavitt MO. Building a value-based health care system. Paper presented April 2008; Washington, DC.

		The Leapfrog Group. The purchaser guide to value-driven health care. www.leapfroggroup.org/media/file/Employer_Purchaser_Guide_05_11_07.pdf. Accessed November 11, 2013.

		US Department of Health and Human Services archives. http://wayback.archive-it.org/3909/20130927155638/http:/www.hhs.gov/recovery. Accessed November 11, 2013.

		Woolf SH, Kuzel AJ, Dovey SM, et al. A string of mistakes: the importance of cascade analysis in describing, counting, and preventing medical errors. 

		Pew Research Center for the People and the Press. 2002. Pew Internet and American Life Project. http://pewinternet.org/Reports/2002/Search-Engines/Data-Memo.aspx. Published July 3, 2002. Accessed November 11, 2013.

Articles

With the New Year approaching, let's resolve to decrease some of the difficulty with anticoagulant medications by welcoming patients and technology into the patient counseling dialogue.

Patient-Centered Care: Give Patients a Shovel

The American Cancer Society estimates that there will be 1,660,290 newly diagnosed cases of cancer by the conclusion of 2013. Taking the lives of almost 1600 people per day, cancer is the second-leading cause of death in the United States behind heart disease.

 These numbers are staggering, the affected population is widespread, and as such, this is an issue that touches the lives of most of us. The primary focus for these newly diagnosed patients is beating cancer. Beyond overcoming cancer, one must also conquer its accompanying maladies. Notably, the second-leading cause of death in patients with active malignancy is arterial and venous thromboembolism (VTE).

The consequences of thromboembolic disease can be catastrophic without proper assessment and care. Patients receiving chemotherapy possess a 47-fold higher risk of dying of VTE over members of the general population.

 With thromboembolism becoming an increasingly common complication of cancer and treatment-related factors—including chemotherapy, hospitalization, and surgical interventions&mdash;it begs the question, how does one improve a cancer patient’s thromboembolic risk? Hypothesis, trial investigation, and evidence-based medicine have begun to shed a light on modern approaches to care.

Much discovery has occurred since Armand Trousseau’s observation of the link between malignancy and cancer in 1865.

 Insight into the connection between tumor biology, inflammation, and coagulation pathway activation has been gained. The meaning of Trousseau’s Syndrome has evolved with the greater understanding that tumor cells produce a variety of procoagulant factors, such as cysteine proteases and tissue factor, that release proinflammatory and proangiogenic cytokines. The upregulation of angiogenesis accompanied by the prothrombotic state in cancer leads to an aggressive tumor biology whereby cancer progression, metastasis, and mortality can result.

The CLOT trial, which demonstrated a 52% reduction in the probability of symptomatic recurrent VTE, led us to the breakthrough that treatment with low-molecular-weight heparin (LMWH) monotherapy is superior to oral anticoagulation for patients with active cancer.

 Furthermore, as advancements are made to understand underlying mechanisms, there is some evidence that LMWH might have anti-angiogenic benefits in addition to the antithrombotic properties for which it is known.

The risk of clot development is highest within the first 6 months after diagnosis. That said, risk is variable among the cancer population and can be stratified based on cancer-, treatment-, and patient-related factors. As a clinical assessment aid, a simple predictive model was developed to assess the risk of clot development using characteristics such as cancer site; readily available biomarkers such as platelet count, hemoglobin levels, and leukocyte count; and body mass index.

 With funding from the National Institutes of Health, this scoring tool has been validated to detect high-risk outpatients who may be suitable candidates for thromboprophylaxis.

It is well established that treatment and prophylaxis are efficacious in the noncancer population bearing risk of thrombosis; however, are prophylactic measures warranted and safe for use within the high-risk cancer population? Two of the largest studies to date, PROTECHT and SAVE-ONCO, assessed the use of anticoagulant prophylaxis in 1150 and 3212 ambulatory cancer patients with chemotherapy, respectively.

 Unfortunately, neither of the therapeutic options utilized is available for use within the United States. It is notable that extended prophylactic treatment may reduce the risk of thromboembolic events without an increase in major bleeding. Despite the significant reduction in VTE displayed within these trials, the event rates were not high enough for the clinical adoption of extended prophylaxis as a standard of care practice for high-risk patients.

Attention to prophylactic measures has heightened, and efficacy has been observed. Still, the American Society of Clinical Oncology Clinical Guideline 2013 Update does not recommend routine pharmacologic thromboprophylaxis in cancer outpatients. However, a new caveat—dissimilar from the former 2007 recommendations&mdash;is that clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy.

 While the evidence is accumulating surrounding cancer-associated thrombosis in terms of its pathogenesis, risk assessment, and trial-related findings, it is important to apply the tools and knowledge acquired thus far to improve patient outcomes and quality of life in high-risk cancer populations. Proper application of these valuable achievements may positively impact the burden of VTE in cancer patients.

Dr. Stevens is an advanced practice anticoagulation pharmacist for the Partners Healthcare System and an adjunct clinical assistant professor of pharmacy at Northeastern University’s Bouvé College of Health Sciences in Boston, MA. This column’s information is based on current studies but may be updated without notice with newer studies or with different populations.

. www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2013/index. Accessed October 30, 2013.

		Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. 

		Trousseau A. Phlegmasia alba dolens. Clinique medicinale de l'Hotel-Dieu de Paris. London: The New Sydenham Society; 1865.

		Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. 

		Mousa SA, Petersen LJ. Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. 

		Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis.

		Agnelli G, Gussoni G, Bianchini C, et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. 

		Agnelli G, George DJ, Kakkar AK, et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. 

		Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American society of clinical oncology clinical practice guideline update. 

Cancer patients must also contend with a range of accompanying maladies, including arterial and venous thromboembolism.

Progress in Cancer-Associated Thromboembolism

The recent evolution of antithrombotic therapy has led many clinicians, patients, and researchers to believe that there may be a “light at the end of the tunnel” with respect to the burden of anticoagulation management. Recent evidence shows that the burden has begun to be lifted for indications such as atrial fibrillation and venous thromboembolism: trials have demonstrated noninferiority and, in some instances, superiority of novel oral therapies versus warfarin.

On the heels of these findings is the thought that the 4 million patients (and growing) who have received a prosthetic heart valve replacement might benefit from these agents. Recent preclinical studies suggested a favorable trend toward efficacy in the mechanical valve population.

 This trend may have been discredited by Eikelboom et al with the early termination of the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement (RE-ALIGN).

 The initial study was slated for 12 weeks, with the option to participate in an extension trial of up to 84 months. Patients were randomized to the dabigatran arm for either 3 to 7 days or >3 months after valve-replacement surgery or to the warfarin arm.

With the primary aim of prevention of thromboembolic complications in patients with mechanical heart valves, it was found that patients enrolled in the dabigatran arms experienced excess thromboembolic and bleeding events compared with patients in the warfarin arm. Notably, the majority of patients experiencing major bleeding episodes (pericardial bleeding within 2 weeks after surgery) or thromboembolic events (typically within the first 90 days) were patients who had undergone more recent surgical intervention.

The FDA and European Medicines Agency recommendations against the use of dabigatran in the mechanical heart valve population stand and have likely been reinforced by these results. While it is unlikely that this patient population will reap the benefits of what was seemingly the ideal anticoagulant, alternatively, a viable option for improvement in quality of life on warfarin may be patient self-testing and/or patient self-management of the international normalized ratio (INR).

Practical Considerations for Diabetics on Antithrombotics

It is well known that diabetic patients are at risk for micro- and macrovascular complications. Coronary artery disease, peripheral artery disease, and cerebrovascular disease are among the most common arterial complications affecting diabetics that result in antiplatelet therapy. Less eminent is the risk of venous thrombosis within this population. Taking into account the progression of vascular compromise in a diabetic patient, one might recall that hyperglycemia can result in endothelial dysfunction, whereby vascular tone and blood flow may become compromised. Metabolic irregularities may lead to decreased homeostasis of calcium, nitric oxide, and other factors, resulting in platelet dysfunction. Cessation of homeostatic function can cause increased production of procoagulants and a decrease in endogenous anticoagulants, leading to hypercoagulability.

Pair these anomalous occurrences alongside the concepts proposed via Virchow’s triad—that is, hypercoagulability, hemodynamic variance (eg, stasis or turbulence of blood flow), and endothelial injury or dysfunction&mdash;and you will find the recipe for thrombosis.

 As an additional consideration, many patients have comorbidities; thus it is possible that a patient with diabetes may also have atrial fibrillation (AF). As defined within the widely used CHADS

 risk-scoring system (whereby points are assigned for congestive heart failure, hypertension, age older than 75 years, diabetes mellitus, and previous stroke/transient ischemic attack) or the more recently recognized CHA

VASc risk-scoring system (which assigns additional points for vascular disease such as myocardial infarction, peripheral arterial disease, or aortic plaque; stratification based on an age range of 65-74 years; and female gender), for AF patients bearing a score of 2 or 1, respectively, the preferred treatment recommendation is an oral anticoagulant.

Given the nature of disease and its complications, it is probable that diabetic patients will receive dual, and potentially triple, antithrombotic therapy. In these instances, individual risk versus benefit should be a consideration. CHADS

VASc) assessment in conjunction with the patient’s HAS-BLED bleeding risk should be compared. Other considerations are potentially tighter control of the INR (eg, 2.0 to 2.5) and a reduction in aspirin dosage to <100 mg when used in conjunction with dual and triple therapies to decrease the risk of bleeding consequences.

Ronelle E. Stevens, PharmD, RPh, CACP, is an advanced practice anticoagulation pharmacist for the Partners Healthcare System and an adjunct clinical assistant professor of pharmacy at Northeastern University’s Bouvé College of Health Sciences in Boston, MA. This column’s information is based on current studies but may be updated without notice with newer studies or with different populations.

		Maegdefessel L, Linde T, Krapiec F, et al. In vitro comparison of dabigatran, unfractionated heparin, and low-molecular weight heparin in preventing thrombus formation on mechanical heart valves.

		McKellar SH, Abel S, Camp CL, Suri RM, Ereth MH, Schaff HV. Effectiveness of dabigatran etexilate for thromboprophylaxis of mechanical heart valves. 

		Schomburg JL, Medina EM, Lahti MT, Bianco RW. Dabigatran versus warfarin after mechanical mitral valve replacement in the swine model. 

		Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves [published online August 31, 2013]. 

		Wessels PF. Anticoagulation therapy in diabetic patients. S Afr J Diabetes Vasc Dis. 2012;9:6-7.

		Lip G, Huber K, Andreotti F, et al. European Society of Cardiology Working Group on Thrombosis. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/ stenting. 

		Faxon DP, Eikelboom JW, Berger PB, et al. Anti-thrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: a North-American perspective. 

Issues in anticoagulation relating to mechanical valve replacement and diabetes patients on antithrombotics.

Mechanical Valve Replacement and Diabetics on Antithrombotics

More than 300,000 US patients are admitted annually for upper gastrointestinal bleeding.

By the time a patient presents to the emergency department with melena, hematemesis, or worse, hematochezia, he or she is already among the population of >300,000 who are admitted annually for upper gastrointestinal (GI) bleeding in the United States. Surprisingly, this number surpasses admissions for congestive heart failure and deep vein thrombosis. Additionally, the associated hospitalization and complications can drive up health care costs by as much as $2.5 billion.

The upper GI tract begins at the esophagus and concludes at the ligament of Treitz, with 60% of bleeding occurrences related to peptic ulcer disease (secondary to 

 infection or long-term use of a nonsteroidal anti-inflammatory drug [NSAID]).

 Other causes may be attributed to gastroduodenal erosion, variceal sources, and to a lesser extent, Mallory-Weiss tears. Medications (eg, NSAIDs, thienopyridines, selective serotonin reuptake inhibitors, antithrombotic agents) are among the most common precipitants that further increase the risk of GI bleeding complications.

Patients are increasingly managed on double- and triple-antithrombotic therapy combinations due to their cardiac benefit. Although concurrent use may be advantageous with respect to overall mortality rates, it is important to factor in the additive risk of bleeding complications. One of the most common complications of anticoagulant therapy is GI hemorrhage. The literature suggests that patients on long-term warfarin therapy with an international normalized ratio (INR) goal of 2.0 to 3.0 are predisposed to a 2- to 5-fold increased risk of GI bleeding episodes.

 Aspirin use alone may double the risk of GI bleeding at a dose as low as 75 mg, while quadrupling the risk at a dose of 300 mg. The protective and restorative properties of prostaglandins within the GI tract are decreased with aspirin use, thereby predisposing patients to the development of duodenal ulcers.

Bleeding rates can be decreased via optimization with alternative medication regimens. As shown in the CAPRIE (clopidogrel versus aspirin in patients at risk of ischaemic events) trial, the use of antiplatelet medications (ie, clopidogrel) in those unable to tolerate aspirin may decrease the incidence of major GI bleeding.

 The indefinite use of proton pump inhibitors (PPIs) in conjunction with NSAIDs has been shown to decrease the bleeding. Cyclooxygenase-selective NSAIDs, such as celecoxib, plus a PPI might also provide greater gastroprotection versus nonselective NSAIDs. Such modifications do not pose a benefit to a patient’s mortality; however, the prevention of future bleeding events and quality of life are viable considerations.

Although as many as 80% of these bleeding events can resolve without treatment, acute upper GI bleeding can be life threatening, accounting for a fatality case rate of 7% to 10% of annual hospital admissions, thus requiring immediate assessment.

 Ideally, patients should undergo endoscopy within 24 hours after an upper GI bleeding episode. Patients seen sooner versus later will likely require fewer transfusions.

 Prompt presentation can aid in proper identification of the bleeding site and extent, further aiding in appropriate diagnosis and treatment planning.

Should the need for endoscopic evaluation arise amid long-term anticoagulation therapy for chronic indications, evidence and expert consensus suggest that patients may safely undergo endoscopy while remaining within their therapeutic INR range of 2.0 to 3.0. Exceptions exist, however, and per the American Society for Gastrointestinal Endoscopy guidelines, the urgency for endoscopy must be considered. Factors to assess include the risks associated with the antithrombotic therapy, the risk of interventional bleeding, and the resultant thromboembolic event that could result with cessation of therapy.

On initiation of long-term antithrombotic therapy, patients should be evaluated for and counseled about risk factors, such as ulcers, for upper GI bleeding. Furthermore, it is important to ascertain patients’ medical history and reconcile current medication use to assess the risk for bleeding or possible re-bleeding events. Early warning signs and symptoms of GI insult should be discussed at the initiation of therapy.

Given the complications, the scales are uneven, as GI risk and cardiac benefit are not easily balanced. Patient counseling during inpatient stay and throughout outpatient decisions is key to improving outcomes and decreasing hospital visits. Patient counseling and care need to be patient-centric. Health care providers can continue to act as resources by educating patients to be mindful of the risks associated with their care and optimizing their outcomes via timely follow-up.

Dr. Stevens is an advanced practice anticoagulation pharmacist for the Partners Healthcare System and an adjunct clinical assistant professor of pharmacy at Northeastern University’s Bouvé College of Health Sciences in Boston, Massachusetts. This column’s information is based on current studies and references, but it may be updated without notice with newer studies or with different populations.

		AHRQ QI. Inpatient quality indicators #18: technical specifications: gastrointestinal hemorrhage mortality rate [version 4.4]. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); March 2012:2.

		Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. 

		Albeldawi M, Qadeer MA, Vargo JJ. Managing acute upper GI bleeding, preventing recurrences.

		Shorr RI, Ray WA, Daugherty JR, et al. Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease. 

		Weil J, Colin-Jones D, Langman M, et al. Prophylactic aspirin and risk of peptic ulcer bleeding. 

		CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). 

		Berger JS, Stebbins A, Granger CB, et al. Initial aspirin dose and outcome among ST-elevation myocardial infarction patients treated with fibrinolytic therapy. 

		Hunt RH, Bazzoli F. Should NSAID/low dose aspirin takers be tested routinely for H. Pylori infection and treated if positive? implications for primary risk of ulcer and ulcer relapse after initial healing. 

		Bjorkman DJ, Zaman A, Fennerty MB, et al. Urgent vs elective endoscopy for acute non-variceal upper-GI bleeding: an effectiveness study. 

		ASGE Standards of Practice Committee. Management of antithrombotic agents for endoscopic procedures.

More than 300,000 US patients are admitted annually for upper gastrointestinal bleeding.
