Jennifer Nessel

® Insights series titled “Proper Dosing of Anticoagulants in CAD and PAD,” Paul P. Dobesh, PharmD, FCCP, BCPS, professor in the Department of Pharmacy Practice and Science at the University of Nebraska College of Pharmacy in Omaha, and James B. Groce, PharmD, CACP, a professor of pharmacy at Campbell University College of Pharmacy & Health Sciences in Buies Creek, North Carolina, and a clinical pharmacy specialist (anticoagulation) at Cone Health in Greensboro, North Carolina, discussed the treatment and dosing of anticoagulants in patients who have coronary artery disease (CAD) with or without peripheral arterial disease (PAD). The series can be found at 

Dobesh defined PAD as an atherosclerotic disease that exists in the large, peripheral vessels of the legs, whereas CAD is an atherosclerotic disease that exists in the coronary arteries. The typical symptoms of CAD are angina or chest pain and even acute plaque rupture that leads to an acute coronary syndrome (ACS). Among patients with PAD, the most common presentation is intermittent claudication, which occurs when they walk. Some men experience discoloration or a loss of feeling in their legs due to loss of blood flow.

When asked about the prevalence of these diseases and what patient populations they affect, Groce said that more than 1 in 3 adult patients in the United States will have at least 1 type of vascular disease. Additionally, 16.5 million adults in the United States have coronary heart disease, and the estimated annual incidence of heart attack or myocardial infarction (MI) is about 580,000 new heart attacks and 210,000 recurrent heart attacks each year. PAD affects about 8.5 million patients, and 80% will have intermittent claudication brought on by increased vascular demand when exercising within 5 years of their initial diagnosis.

The primary prevention for these diseases is complicated and centers on identifying risk, according to Dobesh. These risk factors include diabetes, dyslipidemia, hypertension, and smoking. After these risk factors are alleviated, mortality falls. Dobesh also suggested that pharmacists remain vigilant in recognizing risk factors such as age and family history.

Results of recent studies published in the New England Journal of Medicine showed that aspirin for primary prevention may not play as big a role as previously expected. Newer research into hypertension and lipids shows that the addition of low-dose aspirin does not provide the benefits previously thought to occur. An obvious risk of bleeding exists, so the role of aspirin in primary prevention for coronary disease seems to be limited, according to Dobesh.

In PAD, the lower-level prevention recommendation is an ankle-brachial index (ABI), in which blood pressure (BP) is taken from the leg, which can diagnose atherosclerosis noninvasively. Data suggest that for patients with asymptomatic PAD based simply on an ABI, aspirin might be beneficial.

The experts then discussed the recommended approaches to managing CAD and/or PAD in patients, including a review of the guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA). For patients who had an ACS or a coronary event, dual antiplatelet therapy is a grade 1A recommendation. Physicians should conduct this treatment for a year, regardless of whether a stent is used, according to Dobesh. These patients are then treated with a high-intensity statin to control their BP and urged to stop smoking.

“For other things, like giving [angiotensin-converting enzyme (ACE) inhibitor therapy], it doesn’t probably matter [whether] it’s an ACE inhibitor or an angiotensin receptor blocker [ARB]. Several studies have shown that they have what we call a vasculoprotective effect…,” Dobesh said. He added that patients with stable ischemic heart disease do not necessarily need dual antiplatelet therapy but should be on aspirin.

The goal is to control the episodes of chest pain with a method to lower the heart rate, such as a β-blocker or a verapamil-diltiazem type of calcium channel blocker. Physicians could add other agents, such as dihydropyridine calcium channel blockers, long-acting nitrates, and even ranolazine.

“Chronic PAD has been, unfortunately, very woefully, poorly studied. Aspirin right now is the only thing we’ve ever had that’s been shown to reduce cardiovascular [CV] events,” Dobesh said.

“Again, remember that if you get atherosclerosis in your peripheral arteries, especially enough to give you symptomatic disease, you probably have it in your coronaries, even though you may not have symptoms, and you probably have it in your cerebral vessels. It’s a systemic disease,” Dobesh added. “Really, all we have right now is aspirin in those patients.”

In controlling symptoms, cilostazol does not change CV events but improves walking distance. Other options include carnitine and propionyl-L-carnitine, but those have yielded mixed results. Patients may undergo procedures, but that is not necessarily a guideline.

“The largest study you’re going to find in this area [includes fewer than] than 100 patients. There’s just not good evidence about what to do in this setting, and, I think the patients [with PAD] have really been neglected when it comes to trying to find a way to better their outcomes,” Dobesh said.

Nevertheless, health care providers are ensuring that treatment involves adequate antithrombotic therapy. After that, they focus on ACEs, ARBs, β-blockers, and statins. For patients with PAD, the only treatments are aspirin and perhaps an exercise program.

The key to identifying these patients, Dobesh said, is a careful review of the problem and then contextualizing it. Additionally, practitioners must ensure that one-off orders are for the right drug, patient, indication, and dose.

“We liken it to not just medication reconciliation but medication reconciliation tied to an appropriate indication on the problem list. And when we see the absence, based on a problem list, of a certain drug therapy that we know should be present, it really is incumbent upon us as pharmacists… to make an intervention by calling the provider and giving what would be recommended drug therapy for that patient,” Dobesh said.

The experts then discussed the COMPASS trial (NCT01776424), a landmark study of more than 20,000 patients across 40 countries and more than 300 sites. The study included patients who had stable coronary disease. These patients were not within their first year of dual antiplatelet therapy and were outside a year of their ACS event. About 91% of the participants had coronary disease, 27% had PAD, and 17% had both, according to Dobesh.

The participants were well controlled, with more than 90% having received ACE inhibition therapy, β-blockers, and lipid-lowering therapy. They were randomized to aspirin 100 mL as a standard of care and rivaroxaban (2.5 mL twice daily).

The primary outcomes were CV death, MI, stroke, and a modified definition of International Society on Thrombosis and Haemostasis major bleeding. After a data and safety monitoring board modified half the data, or about 1100 outcomes, the study was halted because of an ethical question related to the standard of care.

“The standard of care was beaten so badly that the study had to be stopped early by the data and safety monitoring board. There was a 24% relative reduction in CV death, MI, and stroke, favoring aspirin with low-dose rivaroxaban as opposed to aspirin by itself…,” Dobesh said. “The aspirin bar was always bigger than the low-dose rivaroxaban and aspirin arm. So there was always a benefit in each one of those.

“What’s interesting is MI was…reduced by 14%, [and] that was probably the one that was impacted the least, but there was a 22% significant reduction in cardiovascular death; that was statistically significant by itself,” Dobesh noted.

To implement the outcomes of this study, providers should be aware of what they mean for patients, Dobesh said. In other words, for the ACC and the AHA to incorporate these results into their guidelines, the role of the antithrombotic drug with the antiplatelet agent should be understood and implemented. The European Society of Cardiology has already accomplished this through its guidelines for death prevention in patients with CAD on including an antiplatelet agent and adding a second agent of an antithrombotic drug per the COMPASS clinical trial: rivaroxaban, 2.5 mL twice daily, with concomitant aspirin.

Ultimately, the experts agreed that communication is incredibly valuable when discussing guidelines and recommendations. “For so long we’ve accepted as status quo the role simply of an antiplatelet agent. And now I think with these evidences that have emerged with respect to both efficacy and safety, we should really give thought to being a part of the role of seeing that these patients now are afforded not only antiplatelet protection but [also] an antithrombotic agent combined with aspirin. So I think that’s the role that we can certainly play as pharmacists,” Groce concluded.

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In a Pharmacy Times® Insights series, 2 experts agree that communication is incredibly valuable when discussing guidelines and recommendations.

Pharmacists Address Proper Dosing of Anticoagulants in CAD and PAD

AS CASES OF coronavirus disease 2019 (COVID-19) continue to spread throughout the United States, health care providers have moved to remote working conditions to ensure the safety of their staff and patients.

For Nancy Crowell, PharmD, senior vice president of operations for Senderra Specialty Pharmacy, one of the advantages of specialty pharmacy is the ability to work remotely without compromising the care that pharmacists give to their patients. Crowell noted that specialty pharmacies are different from retail or community pharmacies because communication with patients is largely by phone.

“We don’t have to do anything really differently in [the] specialty pharmacy world to address the needs of the crisis other than activating a few of our part-time pharmacists to come in and help us handle the call volume,” she told 

. “It is important that the strains and barriers, financial or otherwise, are addressed and handled up front to allow pharmacists to continue caring for patients who are vulnerable at this time.”

Specialty pharmacists play an integral role in preventing disease contraction in vulnerable patients, largely those who are over the age of 65 years or immunosuppressed with comorbidities. These patients have a higher risk for contracting the virus, so Senderra is emphasizing to their staff the importance of sheltering in place to limit exposure until a vaccine is available to prevent the spread.

According to Sheila Arquette, RPh, executive director at the National Association of Specialty Pharmacy (NASP), specialty pharmacy is uniquely positioned by virtue of its established operational model to help protect vulnerable patients across the United States against COVID-19.

“Specialty pharmacies utilize technologies that allow remote patient education and management and deliver medications via the mail or courier promoting patient and pharmacy team member safety. Specialty pharmacies currently possess the operational infrastructure and capabilities to ensure patients can continue to receive their medications and essential support services without interruption and remain adherent to their prescribed drug regimens,” Arquette said to 

In addition to establishing their own COVID-19 resource section on their website, NASP is collaborating with broader pharmacy, drug delivery system, and supply chain communities. They are also working with the Trump administration, Congress, the Centers for Medicare & Medicaid Services, the FDA, various state boards of pharmacy, and state and local officials. This effort is to ensure that patients continue to receive their medication without interruptions, that members have access to the personal protective equipment they need to limit exposure, and that management restrictions for payer-pharmacy benefit managers are relaxed. NASP's efforts also ensure that off-label treatment and recognized medication experts have the support to address inappropriate prescribing and prophylactic use, according to Arquette.

To help their vulnerable patients, Senderra’s pharmacists are given up-to-date information on COVID-19 and are easily accessible to speak with patients directly during the pandemic.

“Our pharmacists can offer valuable lifesaving information and tips for staying healthy as well as working with people to boost their immune system, especially with the medications that we work with,” Crowell said. “It’s imperative that we protect our pharmacy staff, keep them safe and healthy, so that they remain an active part of the health care team during this time. So, we monitor all our staff for sickness, making sure that they stay home if they don’t feel well, [and] follow guidelines for social distancing. …We’re [also] disinfecting counters as well as desks.”

Carmine DeNardo, RPh, president and chief executive officer of ReCept Pharmacy, said that his pharmacy has been committed to the unique role that specialty pharmacists play in providing customized services that enhance patient outcomes.

“As this ever-changing health care landscape of COVID-19 shifts and unfolds, we believe that the communication and empathy we have established with our patients will cultivate an environment of clarity and cooperation for them rather than one of confusion and panic. Our patients know us and trust us—they know we will be there for them to help make them feel better however we can,” DeNardo told 

DeNardo noted that ReCept implemented an infection disease continuity plan early on in the COVID-19 outbreak.

“We have clearly defined the measures needed to safeguard our seamless continuity of care. By following the CDC guidelines and protocols from public health officials, our pharmacy teams have taken precautionary and preventive actions to make the working environment as clean and protected as possible,” DeNardo said.

In addition to counseling patients to boost their immune system by getting plenty of sleep, sticking to a normal schedule, eating healthfully, and limiting the intake of processed foods and alcohol, Senderra is prepared with a business model that allows them to support patients remotely and deliver medication via the mail at no cost. Crowell said this promotes shelter-in-place guidelines, limiting patient and pharmacy staff exposure risk.

According to Crowell, medication adherence may be affected by the current COVID-19 pandemic and stopping medication can be just as or more life-threatening than the virus itself. Senderra’s pharmacists want their patients to discuss a plan of action with their health care provider and to not stop their medication unless they have had a consultation. Medication adherence is vital, so pharmacists should help to ease their patients’ concerns and keep them from stopping important treatments.

“As an essential service, our pharmacy has been solely focused on our patients, assuring them that we are here, we are open. Whether it means bringing their medications out directly to their car or offering free delivery right to their doorstep or advocating for uninterrupted accessibility to their medications, ReCept puts our patients’ needs above all else. Our staff has risen up to face this challenge on behalf of our most valued asset, our patients,” she said.

Crowell noted that it is incumbent on specialty pharmacies to manage their staff members’ and patients’ mental health as well, by working to calm their fears and to assuage their concerns surrounding COVID-19.

“For our industry to continue to provide all of these services to our patients, we’ve got to keep our staff and our pharmacist team healthy and educated so that we can be there for the patient, to reassure the patient, and to give them sound advice,” she said. “Without that, we can’t create the sound business that can be here for those patients. This crisis will come to an end at some point, and it’s very important that we are able to maintain that sound business structure, so we’ll be there just as we’ve been here for so many years taking care of patients.”

One of the advantages of specialty pharmacy is the ability to work remotely without compromising the care that pharmacists give to their patients.

Specialty Pharmacies Continue Assisting Patients Amid COVID-19

 titled “Proper Dosing of Anticoagulants in CAD and PAD,” Paul P. Dobesh, PharmD, FCCP, BCPS, professor in the Department of Pharmacy Practice and Science at the University of Nebraska College of Pharmacy in Omaha, and James B. Groce, PharmD, CACP, a professor of pharmacy at Campbell University College of Pharmacy & Health Sciences in Buies Creek, North Carolina, and a clinical pharmacy specialist (anticoagulation) at Cone Health in Greensboro, North Carolina, discussed several topics regarding the proper treatment and dosing of anticoagulants in patients who have coronary artery disease (CAD) with or without peripheral arterial disease (PAD).

Dobesh defined PAD as an atherosclerotic disease that exists in the large, peripheral vessels of the legs, whereas CAD is an atherosclerotic disease that exists in the coronary arteries. The typical symptoms for patients experiencing CAD are angina or chest pain and even acute plaque rupture that leads to an acute coronary syndrome (ACS). Among patients with PAD, the most common presentation is intermittent claudication, which occurs when they walk. Some men experience discoloration or a loss of feeling in their legs due to loss of blood flow.

Results of recent studies published in the 

 showed that aspirin for primary prevention may not play as big a role as previously expected. Newer research into hypertension and lipids shows that the addition of low-dose aspirin does not provide the benefits previously thought to occur. An obvious risk of bleeding exists, so the role of aspirin in primary prevention for coronary disease seems to be limited, according to Dobesh.

In PAD, the lower-level prevention recommendation is an ankle-brachial index (ABI), in which a provider takes blood pressure (BP) from the leg; this is highly beneficial for diagnosing atherosclerosis noninvasively. Data also suggest that for patients who had asymptomatic PAD based simply on an ABI, aspirin might provide some benefits.

The experts then discussed the COMPASS trial (NCT01776424), a landmark study of more than 20,000 patients across 40 countries and more than 300 sites. The study included patients who had stable coronary disease. These patients were not within their first year of dual antiplatelet therapy and were outside a year of their ACS event. About 91% of the participants had coronary disease, 27% had PAD, and 17% had both, according to Dobesh. The participants were well controlled, with more than 90% having received ACE inhibition therapy, β-blockers, and lipid-lowering therapy. They were randomized to aspirin 100 mL as a standard of care and rivaroxaban (2.5 mL twice daily).

The primary outcomes were CV death, MI, stroke, and a modified definition of International Society on Thrombosis and Haemostasis major bleeding. After a data and safety monitoring board modified half the data, or about 1100 outcomes, the study was halted because of an ethical question related to the standardof care.

Pharmacists address proper dosing of anticoagulants in CAD and PAD In a Pharmacy Times® Insights series, 2 experts agree that communication is incredibly valuable when discussing guidelines and recommendations.

Researchers have developed a new way to map the molecules on tumor cells that flag their presence to the immune system. Their findings could make commonly used immunotherapy treatments effective for a larger population of patients with cancer, according to a study published in 

Certain cancer immunotherapy treatments work by targeting short pieces of proteins, known as peptides, which are displayed on the surface of cancer cells. Peptides are presented on the cell surface by human leukocyte antigens (HLAs), which have many different types. However, immunotherapy research tends to focus on a small subset of HLAs only. As not all patients with cancer produce these HLAs, they are unable to benefit from existing HLA-based immunotherapies.

"Most studies have focused on HLA proteins that are commonly found in the general population. We have developed a new technique that allows the sampling of underrepresented HLA proteins to find peptides or antigens that can induce an anti-tumor immune response. We can then stimulate the patient's own immune cells with those peptides and give them back to the patient to help treat their cancer,” said Kenji Murata, co-first author, in a press release.

The researchers isolated T cells from 8 patients with melanoma. This patient group spanned 25 different types of HLAs, allowing the team to analyze T cell interactions with more than 800 different antigen peptides. The 8 patient samples were positive for at least 1 of the peptide-HLA combinations. The methods developed here also allowed the team to discover new peptides recognized by the T cells.

Next, the team explored whether the T cells that reacted to the peptides could cause an immune response by measuring the production of interferons. All except 2 of the antigens stimulated the T cells to produce interferons, as well as to stimulate the cells to increase in number. These effects were made more robust by adding to the T cells an artificially engineered antigen-presenting cell (APC) bearing the same antigen, which is a common strategy to stimulate T cells, according to the study.

In the next stage, the team used the artificial APCs to find the exact immunogenic signal that stimulated the T cells from melanoma patients. They found novel peptide fragments related to 2 different antigens, called MART1 and NY-ESO1, which are known to contain immunological hotspots, according to the study.

The researchers examined whether they could engineer T cells to target these novel antigens by taking cells that react against the novel antigens and cloning their T cell receptor (TCR) genes. TCRs are cell-surface proteins that allow T cells to react to antigens. When they added these cloned TCR genes back into newly isolated T cells, they found that the cells were able to recognize and react to the tumor cells.

"By querying human melanoma-derived T cells and using novel HLA proteins bearing common tumor antigens, we have been able to discover both new and existing immunologically active antigens in tumors. Our strategy allows for a more complete examination of the immune response and development of novel cancer vaccines and immunotherapies for a broader group of patients not limited by HLA prevalence or tumor mutation burden,” said senior author Naoto Hirano, in a press release.

Comprehensive tumor immunity map opens up immunotherapy to more patients. EurekAlert website. Published April 21, 2020. 

https://www.eurekalert.org/pub_releases/2020-04/e-cti042120.php

Researchers have developed a new way to map the molecules on tumor cells that flag their presence to the immune system.