Achieving adherence to lipid-lowering regimens

Journal of Clinical Lipidology (2013) 7, 4–13

Clinical Lipidology Roundtable Discussion

Achieving adherence to lipid-lowering regimens W. Virgil Brown, MD*, Terry A. Jacobson, MD, Lynne T. Braun, PhD, CNP Editor–in–Chief, The Journal of Clinical Lipidology, Charles Howard Candler Professor of Internal Medicine Emeritus, Emory University School of Medicine, 1670 Clairmont Road, Atlanta, GA 30033, USA (Dr. Brown); Director, Office of Health Promotion and Disease Prevention, Emory University, Atlanta, GA 30303, USA (Dr. Jacobson); and Nurse Practitioner, Preventive Cardiology Center and the Heart Center for Women, Rush University Medical Center, Chicago, IL 60612, USA (Dr. Braun)

Opening/Introductions There are few preventive treatment regimens as well documented to be effective in reducing cardiovascular disease as those which lower blood concentrations of low-density lipoprotein cholesterol (LDL-C). Both lifestyle changes and medications are effective and very safe. However, far too many patients fail to fully sustain these treatments for more than a few months. Recent surveys indicate that more than 50% of patients are no longer taking statins 1 year after receiving a prescription. Drugs for high blood pressure are discontinued at a similar rate. This problem is a very important and frustrating one that impairs our ability to reduce cardiovascular events. Lynne T. Braun, PhD, CNP (Rush University Medical Center) and Terry A. Jacobson, MD (Emory University School of Medicine) have agreed to share their experiences about improving adherence to lipidlowering regimens in this Roundtable discussion. Dr. Brown: Let’s begin by attempting to quantify the problem. How successful are our efforts to institute a Dr. Braun healthful diet in patients with major risk factors? Dr. Jacobson: The first thing I want to say is everyone is different and that there’s a difference between population * Corresponding author. E-mail address: [email protected] Submitted November 26, 2012. Accepted for publication November 28, 2012.

versus individual strategies. On average, individuals can lower their LDL by 5% to 15% on an ideal diet, but in the real world most individuals are unable to lower it more than 5%. Weight loss is even harder than lowering LDL-C, and the Dr. Brown long-term outcomes data are fairly disappointing. At the end of 1 year, most people are at their baseline weight. I believe that obesity counseling with lifestyle changes is a tougher nut to crack than LDL reduction. An important point is that there are other significant health benefits associated with lifestyle changes besides just weight reduction. Being on a low-fat, high-fiber diet, increasing consumption of fruits and vegetables, and increasing physical activity are all associated with improved overall health outcomes. There has been too much of a focus on weight as the major metric for outcomes versus maintaining long-term behavioral changes in diet and physical activity. I am very clear with patients: Make changes in your diet and level of physical activity. If you lose weight, that is great, but if you don’t, as long as you continue to sustain positive lifestyle changes, it still will be positive metabolically for your LDL, blood pressure, insulin resistance, and total well-being. So, I encourage any small behavioral changes that can be sustained. Dr. Braun: I do the same thing. I think that counseling patients on healthy dietary behaviors and a regular exercise program can benefit all risk factors. I tell Dr. Jacobson them that exercise is better than most of

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the medicines that I have them take. After all, diet and physical activity are the cornerstones of primary prevention. Dr. Brown: Is there any evidence that combining an exercise program with dietary change actually achieves more in terms of the goals of weight loss or cholesterol level? Dr. Jacobson: Yes, there are data that any combination of therapies, or therapies that are multimodality, are better than any single therapy. If you talk to obesity experts they say you need both, although dietary change for obesity is still more important than physical activity. With increasing physical activity, we no longer use the term exercise, since it’s a remnant of the old days where we told you to exercise to 85% of your heart rate max to get a cardiovascular training effect. Unfortunately, few individuals could do that, and so no one did it, and so now we’re just saying, ‘‘Hey, just be active. Movement is medicine.’’ Walking is just as good as any structured physical activity or exercise. Try to do it 30– 60 minutes a day at least 5 days a week. Because exercise can be a pejorative term to some, we put more emphasis on staying physically active and getting your activity in whether at home or work. Dr. Braun: That’s why the term lifestyle physical activity is so important to use. Because we know that there’s physical activity that can be a component of your occupation. It should be a component of what you do during leisure time as well, both of which are very important. I want to add to your comment about the combination of diet and physical activity and the need for using multiple lifestyle changes together to create the desired outcome. When an individual significantly reduces dietary saturated fat, there is a chance that high-density lipoprotein (HDL) levels may decrease. So adding physical activity is very, very important to maintain or hopefully even improve those HDL levels. Dr. Brown: I have seen studies that indicate that the really crucial issue may be the loss of body fat and sometimes with exercise programs, people actually don’t lose weight but they lose fat and gain muscle. Many studies have demonstrated that healthful changes relate best to fat loss not weight loss. There was one done at Duke and another by. Dr. Mary Ellen Sweeney at Emory reporting that fat loss correlated best with blood glucose and triglyceride reductions as well as HDL elevation. And that the really strong studies correlating with the multiple measures including insulin resistance were with body fat loss and that ones that dieted and didn’t do exercise but achieved the same body fat mass loss actually had the same or greater benefit in terms of insulin resistance and lipid levels. So, it is a different approach but the issue I think is to really have a program that a person can buy into and sustain and maybe the end point that we should be measuring is body fat. Dr. Braun: That’s a very good point and something that we have to make clear to our patients because we tell them to know your numbers and to self-monitor, such as to weigh themselves. When they don’t see the scale change, and when the pounds don’t decrease, they can become very frustrated. I immediately follow that up with ‘‘Tell me if you have noticed

5 a change in how your clothes are fitting.’’ They almost always say, ‘‘Oh, absolutely. I can notice a difference.’’ Dr. Jacobson: I think there are multiple metrics for success and with weight loss, it can’t be all or nothing. I reward behavior and I do it consistently. If someone says ‘‘I switched from whole milk to skim milk,’’ I say, ‘‘Fantastic. That’s a specific behavior change.’’ Their cholesterol might not have changed, but they need to know which behaviors they are doing right and which ones they’re doing wrong. It’s not the actual change in knowledge per se that is important; it is the change in their behavior and their actions. They already know whole milk isn’t as good as skim milk. We also forget about praising patients for making small little changes. We kind of come down hard on patients all the time, ‘‘You didn’t do this, and you didn’t do that.’’ This is the wrong approach since it generally does not work. So we need to be more proactive and positive and praise positive behavioral changes. Dr. Braun: I agree and do the same thing. I document those small changes my patients make so that when I review my previous note, I can address it. When we discuss lifestyle changes the next time, often patients will add additional changes they made and I document them again. Dr. Jacobson: And they smile. Dr. Braun: They do. Dr. Jacobson: Because they know that you made it important and that you wrote it down. Dr. Braun: That’s right. Dr. Brown: Are there organizations that are generally available and that might facilitate or strengthen the patients’ ability to sustain long-term adherence to these regimens? Are there ones that you would recommend? Dr. Jacobson: There are a lot of organizations out there that can be useful that range from activities at senior centers and churches to fitness centers employing personal trainers and health coaches. But even the most simple and widely available community programs, like the YMCA, offer a lot of helpful programs. Swimming, exercise, resistance training, aerobics, yoga, nutrition, cooking classes, and so on. Of course there are many topline organizations for weight loss like Weight Watchers, Jenny Craig, etc., and most of them are excellent. I think when a motivated individual is willing to pay to achieve a health benefit, they are more likely to succeed. However, maintaining long-term behavioral change is still the hardest thing. Dr. Braun: I’m a nurse practitioner and I often have more time with my patients than a physician might. Therefore, I have more opportunity to get to know them and to know their lifestyle and how they might best make lifestyle changes. What has worked for them in the past is really important and now they might try something similar. I have had some patients be very successful using Weight Watchers online, and it seems to keep them engaged. They are required to input all of their information so they must be self-directed. Yet other patients might do much better being a part of a more formalized program. I can’t stress enough what it means to get to know your patients and to

6 learn how they work best and what their preferences are. It’s important that we help our patients be successful. Dr. Jacobson: Engaging the community is also very important place to start. In the South, where I live, churches are major change agents and you get one church saying ‘‘Okay, let’s compete with another church for weight loss.’’ Other potential important community resources and programs for change can now be found at places of employment, at schools, and in parks and recreation centers. Dr. Braun: It works. Dr. Jacobson: Even at the macro community level, the Centers for Disease Control and Prevention and other public health groups have begun to talk about making changes even at the level of the neighborhood. Many low-income individuals live in unhealthy neighborhoods without access to parks, access to sources of heart healthy food, or access to safe inexpensive recreational facilities. So communities and public health groups now are trying to be proactive by putting in more parks, more walking lanes, and more bike lanes. So many people may be at a disadvantage for heart healthy behaviors partly because of their unhealthy environment. A simple example is trying to find fresh fruit or vegetables in a store in a disadvantaged community. You talk to the store owner, who says they don’t sell well, they are expensive, and no one wants them. However, you can find every type of unhealthy chip there is in the world and every type of sugary soft drink. So I do think working at different levels in the community is just as important as working directly with health care providers. Although providers are the most important source of health information for patients, the community provides the additional leverage for longstanding behavioral changes. Dr. Braun: I agree that the community is important. I’m a part of an National Institutes of Health–funded study, a walking program for African-American women, where our focus is physical activity adherence. We are using six different community sites in Chicago. At the time we began the study, one of the community sites was on the news as the most violent community in Chicago. Although safety is an important issue, this community became engaged and embraced our program. The hospital in the community promoted the program with their employees and made it part of the employee wellness program. The employees are encouraged to walk during their work hours, and their supervisors often walk with them. When they walk outdoors, the community comes out to cheer them on. This is quite amazing because it was a community that we were almost afraid to go into yet the program has helped to turn things around in a healthful way. Dr. Brown: It seems clear that support groups or just having a buddy or two that work with the patient can help extremely sustain a long term daily or weekly habit of participating in exercise programs. Perhaps that also spills over to dietary adherence as well? Dr. Jacobson: There’s something magical about social support. People sharing experiences can do a lot more than they can individually.

Journal of Clinical Lipidology, Vol 7, No 1, February 2013 Dr. Braun: When I partner with my patients who wish to make behavior changes, I tell them, ‘‘You need to share it with your spouse and your family because they will help and be supportive and encourage you. You should also let your coworkers know so that they can embrace you.’’ Dr. Brown: In the practice of clinical lipidology, the reduction of LDL-C and now non-HDL-C have been our primary goals. Medications are most effective in this effort. Dr. Jacobson, what are your approaches to motivating your patient from the day you prescribe a lipid-lowering medication? Dr. Jacobson: We’ve talked earlier that everyone is an individual and has different beliefs, knowledge, and experiences in taking medicines. So what I try to generally do with a patient is first frame the benefits. I think a lot of people forget to link the drug to the benefits and the benefits are not just lowering cholesterol but the reduction in hard cardiovascular end points. It’s not only living better but living longer. The statins to me are a no brainer. To me, along with aspirin, statins are a wonder drug. Statins have reduced risk in virtually every population ever studied. I will tell a patient ‘‘I have a medicine that will not only lower your cholesterol but will allow you to live longer and live better.’’ There’s probably only a handful of medicines that can do that. Not only do I tell patients about reducing their risk of heart attacks with statins, but I also mention the reduction in stroke. People seem to fear stroke more than they do heart attacks, and this is often a selling point in the elderly. So I talk about the benefits first and connect the drug to the benefits. I tell patients that with this medicine, you have a better chance of not having a heart attack or a stroke, and that you may even live longer. Also I will mention that statins are very effective for lowering cholesterol and that they really have very few side effects. If side effects do occur, I tell patients that they are generally very minor and can be easily managed by generally switching statin drugs or changing doses. So, I’m very positive in my framing and then I say, ‘‘Okay, it’s often hard to take medicines on a regular basis, so what do you do to remember to take your medicines?’’ You try to link taking the medicine to a regular time a day (i.e., morning, before bed time) or to a regular activity such as brushing one’s teeth. Once starting a new medicine, I tell patients to call me if they are having a problem. Don’t stop the medicine immediately, because sometimes it might not be from the medicine. And then I mention that we will periodically monitor them with laboratory tests to assess for both cholesterol lowering and for safety. And so I generally start off with a positive framework when beginning statin therapy, but then I ask, ‘‘Tell me why I’m giving you this medicine,’’ This is what we call a ‘‘teach back.’’ I deal with a lot of people with low-literacy skills, and Dr. Brown, when you worked at the Veterans Affairs (VA), I’m sure it was a similar issue. Can people articulate back to you why they’re taking this medicine and what the benefit is? If they can’t, they’ve probably not understood what you have said and are likely to be

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noncompliant. So I think having the patient articulate back in a teach back, ‘‘why do I take this, when do I take it, what are the benefits for me,’’ is very helpful. Dr. Brown: So it seems important to start positively and to promote the development of some very simple habits that remind the patient of dosing every day? Dr. Braun: I echo everything that you said, Dr. Jacobson. I’d like to add that I also talk about the benefits that go beyond cholesterol lowering and I relate it to what specifically is going on with that patient. If the patient had a recent event, I state that a statin is a lifesaving medication that will help stabilize plaques and prevent plaques from progressing. If the patient has very high LDL levels, we talk about lowering their risk for cardiovascular disease as well as lowering LDL. If the patient is someone with a very strong family history of premature coronary disease, then I again relate the need for medication to their high-risk status. It’s important that we provide our patients a good explanation that they can understand if we choose to treat them with medication. I also believe that the provider/patient relationship is key to facilitating adherence to all recommendations. If we don’t take time upfront and be sure our patients fully understand why we are prescribing a medication and to thoroughly answer their questions, they will go off and might not even fill that prescription, they may stop it after a week or two, and we may never hear from them again or may hear from them a year later and they’ll say, ‘‘Well I decided not to take that medication.’’ It’s so important to say, ‘‘If you’re having second thoughts, if you think you’re experiencing a side effect, call me.’’ If we can’t respond to every patient personally, it’s important to enlist the help of the clinic team. Dr. Brown: I couldn’t agree more. I would never leave home without brushing my teeth and shaving. So placing my medication between my toothpaste and my shaving cream helps my adherence. Dr. Braun: That’s right. Dr. Brown: The other big issue is trying to get over the negative concept of long-term use. Some patients do not hear the message that a regimen is meant to control, not cure, that it should be part of their lives indefinitely. All physicians must have had patients return, off medication, feeling that the prescribed number of pills in the first bottle was the total treatment. Others stop their medications when told that their cholesterol or blood pressure is now at a desirable level. How do you deal with these problems? Dr. Jacobson: A very important point is to tell patients that this is a chronic condition that can be controlled, not cured, and it’s necessary to manage it for a lifetime. It never will disappear, but we can manage it very well. And the longer that we manage it, generally the better the outcome. Meaning you’ll have even greater risk-reduction for heart disease and stroke over time. It is estimated that the 25% risk reduction seen at 5 years in clinical trials might approach 50% after 10 years. I emphasize the long-term lifetime prevention message—and then state, ‘‘Since you’re going to take this for a lifetime, I want to find the best therapy for you that you can easily tolerate.’’

7 Dr. Brown: I often hear the following from my patients: ‘‘My brother said ‘statins causes liver disease and your liver’s going to fail if you take that too long’.’’ Even more common is the attributing aches and pains to statin therapy. Rumors and misinformation about adverse effects are very common. How do you manage that problem? Dr. Braun: I try to address it upfront. A student just commented to me, this week in fact, that a physician she works with doesn’t want to talk about side effects with patients because this will put those side effects in a patient’s head. My response was, ‘‘Then how do you manage what they see hear on TV, what they find on the Internet, and what they receive when they fill their prescription?’’ I feel you have to talk about side effects upfront. Hopefully, patients will trust what you tell them. I talk about the very rare potential for liver toxicity as well as muscle symptoms, both of which I’ll bring up right away. I tell them how very low the incidence is for liver toxicity, that I take care of a lot of people with high cholesterol and I hardly ever see that, and I tell them, ‘‘I will know if it caused a problem before you will know because every time I do a lipid panel, I’ll check the liver enzymes. I may check liver enzymes more often than is recommended.’’ So I order what I call ‘‘safety labs’’ for the patient, especially when I start a medication or increase the dose. Regarding the muscle ache issue, I tell them that it’s a potential side effect, and it does occur. And I tell them that although statins are in the same class of medicines, they are very different drugs from one another, and just because you’ve experienced a side effect from one statin or a certain dose of one statin doesn’t mean that it will be the case with all. So I think that’s very important. And I explain to them, how it really feels, the classic way it feels, ‘‘Have you ever had the flu where you experienced muscle aches?’’ And they’ll usually say, ‘‘Yes.’’ ‘‘That’s really the muscle aches that we’re talking about here, especially the muscles that are closest to your body.’’ I get up out of the chair and I say, ‘‘This would hurt if you were having true muscle aches from your medicine, it would hurt to get up out of a chair because your thighs and your butt would hurt so bad.’’ I try to give them examples of what it is, so they’re not blaming the ache in their left index finger on their statin and stop it. Dr. Jacobson: Providers often think that by telling a patient about potential side effects that they might be opening up a Pandora’s box and that the patient is then going to have these side effects. And I think that’s how many of us were trained years ago. However, the topic of statin safety is very much in the public mindset—this is what people talk about at parties. ‘‘My statin, causes my thigh and leg muscles to hurt when I run, does that happen to you?’’ I think addressing it head-on is helpful. In my practice, there’s generally two different types of patients. There are the kinds of patients who are often older and are used to a more paternalistic approach, and you just tell them what to do and they’ll do it without questions. And then there’s those who are the activated consumers who have a million

8 questions, who actively search the Internet, and have seen the New England Journal of Medicine before you have, and who want more information about side effects. So I think you have to assess someone’s need for information and the type of information that they need. We can no longer shy away from questions about side effects anymore. This whole liver function test (LFT) issue is unfortunately perpetuated by direct-to-consumer (DTC) ads, which mentions the need to talk to your doctor about liver side effects and the need for recurrent monitoring. Many of us believe this is overkill and have scared too many at risk from taking proven agents. Dr. Brown: There some noted British physicians who have said that it’s malpractice to measure LFTs in patients who are taking statins. Since there’s never been a proven case of actual liver toxicity with statins, you’re more likely to cause the patient to stop taking it because it’s an aberrant value. If you tell the patient about a slightly abnormal transaminase value, they are likely to stop their drugs. We know that such values occur frequently without explanation and mean nothing about liver toxicity. Dr. Braun: They ask about that. Dr. Brown: Absolutely. Recently, the Food and Drug Administration (FDA) has markedly reduced emphasis on monitoring for liver toxicity during statin therapy. The Clinical Trials Group at Oxford University in England has looked at the population-based incidence of liver failure in many thousands of people on statins in long-term clinical trials and the incidence of liver failure is no different from the general population. Dr. Jacobson: The National Lipid Association (NLA) actually convened a Task Force on Statin Safety several years ago, and we came up with a conclusion that we were afraid to say directly. Since the background rate of liver failure in the general population was the same as the rate in individuals taking statins, we concluded that there were no data to suggest that LFTs needed to be monitored. We did not know how to phrase this conclusion without directly challenging the FDA or changing the prevailing standard of care. We ended up concluding that you can still get LFTs if you want to but they were not necessary. Unfortunately, the general public now fears the liver side effects of statins more than the risks of having a heart attack and the DTC ads have disproportionately contributed. Although DTC ads effectively increase awareness of high cholesterol, all that patients remember is the disclaimer at the end, about the possibility of liver injury. I do think the FDA and professional societies need to address this issue of liver safety more directly since the public still is unnecessarily concerned. Dr. Braun: I’ve also found that when the liver enzymes do bump a little bit, often times it’s related to the quantity of alcohol intake, and so I need to investigate that and I have to have a heart-to-heart discussion with my patient about it. Dr. Brown: And when people take other medications, not just statins.

Journal of Clinical Lipidology, Vol 7, No 1, February 2013 Dr. Jacobson: Exactly. The thing is the FDA has given several hints about not needing to monitor LFTs. I will give you an example, that when over-the-counter statins came up for FDA review, few or none on their advisory panel had concerns about patients not knowing their LFTs at baseline or not getting medical follow-up for repeat LFT testing. The FDA was more concerned about pregnant women taking statins and people self-monitoring their cholesterol without entering the medical system. Within the FDA, an informal rule for detecting liver injury is referred to as Hy’s law, named after Hy Zimmerman. A drug has a high probability of causing liver damage or liver failure when both the transaminases are elevated and the bilirubin increases twofold the upper limit of normal. Despite the widespread use of statins, this has not been observed with statins in either preclinical testing or in extensive postmarket surveillance. Dr. Brown: We watch for an increase in bilirubin to twice the upper limit of normal with transaminases above three times the upper limit of normal, the so-called Hy’s law for indicating liver damage. There are many causes for such laboratory abnormalities so these findings need careful evaluation, not simply stopping medications. Dr. Jacobson: Unfortunately, we have seen liver failure with many nonstatin drugs, including herbal supplements and nutraceuticals as well as imported drugs not evaluated by the FDA. It really has not happened with statins and statins are one of the most widely used medicines in the world. It’s unfortunate that at-risk patients still think, ‘‘statins may hurt my liver.’’ Dr. Braun: Dr. Jacobson, you mentioned patients who need more information than others. I’ve actually printed out the NLA advisory on statin use and have given it to a few patients who really need the information. Dr. Brown: Do you think we should develop some additional patient educational material? Is there sufficient effective material available to the physician that could help with the problems of patient adherence? Dr. Jacobson: With regard to risk factor control, I believe adherence is the number one problem in the United States right now. Here we have effective medicines that work such as statins, yet a sizable portion of the population is not taking them. The estimates are 50% at 6 months are still taking their statin, 25% at a year. It’s unconscionable for a medicine that’s been so well proven, that has so few side effects not to be taken at all. So I think we need a lot more research on adherence. Also, providers always blame the patient for nonadherence, and they’ll say ‘‘it’s their fault and not my problem.’’ That is a total cop-out. It’s a multifaceted problem that includes the provider, the system of health care delivery, the amount of copay or insurance, the pharmacist, etc. The bottom line, as stated by Dr. Everett Koop, the former Surgeon General, is ‘‘drugs don’t work in people who don’t take them.’’ Even if we had another blockbuster lipid-lowering agent to add to a statin, it pales in comparison in terms of the benefits we would see if we had 100% statin adherence. Yet big pharma is not that interested in adherence research and I’m not quite sure why.

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Dr. Brown: I worked on this 15 years ago at the instigation of a pharmaceutical company. It now appears that they gave up. This maybe because no one ever came up with an idea for health professionals that seemed to solve the problem. Perhaps direct to consumer advertising has been one result? Dr. Braun: I already talked about the need for good communication between the provider or the provider’s office and the patient. When thinking about adherence, if I have an inkling that a patient might not be 100% adherent, I directly ask an adherence question. I say, ‘‘In the last two weeks, you should have had 14 doses of your statin. Tell me in the last two weeks, how many doses you think you took.’’ It’s kind of like the alcohol question. I never say, ‘‘Do you drink alcohol.’’ I say, ‘‘On an average week, how many alcoholic beverages do you have,’’ assuming that most people drink somewhat. I assume that some people are nonadherent some of the time; we have the data to support that. So I say, ‘‘How many days in the last 2 weeks did you take your statin?’’ And if they say 14, I’ll say, ‘‘Great, that’s wonderful,’’ but if they say 12 or 10, then that leads me to explore why. Dr. Brown: We talked about the support groups for lifestyle changes. Are there ways to bring the support group in on the medication issue? Can you involve the family, particularly the spouse? The husband or wife can destroy adherence if they don’t fully understand the issues. Dr. Jacobson: I agree family involvement is key. Getting a spouse, a significant other, a relative, a caretaker, or a friend, involved is very important. It also reinforces other positive behaviors like lifestyle change. We believe that having someone else other than the provider monitor the patient is a very effective strategy. So often we’ll engage the significant other, the spouse, the children, or even the grandkids. I’ve seen this happen a lot with grandchildren, who are looking after grandma and grandpa who are not taking their meds correctly or on time, and they’re on their case. I think support systems are very important and I think it is important to engage them. I think going back to Dr. Braun’s question, I think it’s a very important point about asking patients directly about adherence. If you don’t know or you think a person is nonadherent, you need some objective measure of it. You can look at refill rates, but often we do not have access to pharmacy records. I kind of assume they’re missing doses and I ask in a nonconfrontational manner ‘‘How often have you missed doses in the last month?’’ And very rarely someone will say ‘‘never,’’ Then I follow-up with the question ‘‘what are some of the reasons you missed a dose? What was the problem?’’ You’d be shocked at the responses. Dr. Braun: It certainly lends to getting information, not only about taking their medicine but about many other things in their life. Dr. Jacobson: I’ll tell you what I hear the most often, ‘‘I forgot,’’ of course. ‘‘My routine has changed, I go to bed earlier now,’’ or ‘‘I am always falling asleep before I get a chance to take my medicines,’’ or ‘‘I ran out and did

9 not have time to refill at the pharmacy,’’ etc. It’s often a very simplistic reason and an easy solution. For example, patients who were told to take their statins at night but forgot to, could have been surely dosed at any other time such as in the morning or around a meal. Thus, I explore with every patient what problems they are having adhering to their medicine and what could be done to overcome them. I drive our house officers at Emory crazy about this, since you do not know if someone is having problems with adherence unless you ask. You can’t look at only surrogate markers, such as LDL-C levels, since patients will often religiously take their medicines a week before their visit to impress you on how well they’re doing, but they’re clearly missing the point. I think, it is very important to ask about adherence in a nonjudgmental way so as to allow patients to be honest. ‘‘Yeah I do miss a dose from time to time,’’ or, ‘‘I couldn’t make it to the pharmacy.’’ Refilling prescriptions is a huge issue, something we take for granted. Many older patients can’t make it to the drug store, are too sick, can’t get a ride, and become not adherent for reasons that are fixable. It’s not even the financial issue that they can’t afford the medicine. Simply, if they can’t get it, they obviously can’t take it. Often some patients go weeks without their refills. Dr. Braun: I also agree that involving the family is critical, whether it’s the spouse, significant other, the children, a friend, or whomever, because that’s important not just for taking medication but especially for making lifestyle changes that you’re counseling the patient to do. Once again, others can be supportive, and as a provider, you can have impact on the family as well, not just that patient. Specifically for dyslipidemia, if it’s a first-degree relative that you have involved in counseling, he or she may have the same issues as well. You may someday be seeing the children as patients, so it’s so important to pull that family unit together from the beginning. Dr. Brown: Some physicians involve everyone in the office with the idea of saying something positive to the patient about their medication and their control. The nurse can powerfully reinforce the physician’s efforts in encouraging and supporting adherence. Have there been studies of this or have you also witnessed this effect? Dr. Braun: It’s true, engaging the staff and letting them know that their role with the patient is very important. There are data to show that the more contact either the health care provider or the office staff has with the patient, this helps to improve adherence and to identify problems early on. Often certain problems or issues can be identified before that next visit, so a physician who works with a particular nurse can ask the nurse to make an interim phone call to that patient to see how things might be going and then help problem-solve some of those issues. Sometimes the physicians with whom I work have the patient schedule with me as an interim visit and I can work on lifestyle changes and/or titrate medications. Dr. Jacobson: This whole concept of a team of health care providers trying to keep individuals and groups of

10 individuals healthy is very important, Everyone matters, including your front desk clerk not eating fried chicken or smoking in front of the patients. It’s a culture change. The way I see it is that staff and allied health providers, need to be on the same page as what the essential message is. That includes almost everyone including nurses, nurse practitioners, physician assistants, pharmacists, dieticians, exercise rehab specialists, and even psychologists, who are all part of the team to make you healthy. There’s very good data that a team approach is more effective than an individual provider approach. There’s been at least three or four major studies that really point out how a team approach is much more effective at getting better outcomes, reduced cost, and better adherence. To just mention a few, Kaiser for example, created a team model of chronic care delivery for most chronic diseases, including hyperlipidemia. Nurses and nurse practitioners were doing more than just managing hyperlipidemia at clinic visits; they were working with physicians to contact patients more frequently by phone and address adherence and problem solve in real time. By the end of the intervention they showed they can get more patients to goal and they could do it cheaper. The second thing I want to mention is the use of other allied support staff, including the use of clerks. I’ll give you an example, at Grady Hospital, our county hospital in Atlanta, we asked clerks to ask each patient on every visit, ‘‘Are you a smoker?’’ and record it in the chart. This is called assessing smoking as a fifth vital sign. All of a sudden we were identifying smokers that we either forgot to previously ask or thought we had asked. Our house staff were embarrassed that they didn’t know that a person was still a smoker and that somehow it dropped off their problem list. Thus, anyone can be helpful if we use a team approach. Dr. Braun: I’d like to mention a couple of my colleagues as we talk about this. Kathy Berra recently published a review of nurse case management studies showing that when nurses work in collaboration with physicians, the outcomes are typically excellent. Secondly, the Coach study, funded by the National Institutes of Health, was just published by Dr. Jerilyn Allen in Circulation Quality and Outcomes. This study showed that patients managed by a nurse practitioner/community health worker dyad achieved significantly better improvement in cardiovascular risk factors compared to usual care. Dr. Brown: There are many distractions in this world. We see all sorts of cures advertised that don’t require you to go to the physician or the nurse practitioner. Many over-the-counter agents are being touted as being effective and natural and so on. Do you see that as a problem in adherence to prescribed medications? Dr. Jacobson: Obviously yes. It’s clear there are patients who prefer not to take prescription medications and have the false belief, that if it’s natural, it’s good for you. Red yeast rice comes up all the time as a possible substitute for statins. Despite having more impurities in red yeast rice

Journal of Clinical Lipidology, Vol 7, No 1, February 2013 than pure lovastatin, many patients still would not take prescription lovastatin. I don’t mind patients taking alternative medicines, as long as they use them on top of proven medications such as statins. Also, one needs to be sure that that they don’t have any significant drug interactions or are known to cause harm. St. John’s wort, for example, can interfere with the cytochrome metabolism of simvastatin. For those patients who want to continue to maximize dietary therapy or want to try various new supplements instead of a statin, I make it very clear that I will give them a finite amount of time to get their LDL-C to the goal. If they can’t obtain that goal within the specific time frame, I make it very clear that the next step would be drug therapy. Dr. Braun: Some patients who can’t afford it are spending a lot of money on supplements. They might even complain about the cost of prescription medications. Sometimes I’ll ask them what it’s costing them for the supplements and I’ll say to them, ‘‘Do you know that what you’re taking is not regulated by any organization? You really can’t be sure what’s on the label is what you are getting.’’ The other challenge is that sometimes they’ll purchase something from a website and it has 20 different supplements or herbs in it so I’ll say to them, ‘‘Okay, e-mail me the information, I’ll have to look it up to be sure it doesn’t interact with your prescription medicines.’’ Dr. Brown: You can take your statin and eat fungus at the same time but you will not know your actual dose with red yeast rice. The alternative is to take your prescribed statin, which has been purified, tested in clinical trials, and approved by the FDA. This quality of being natural is highly valued by some patients. They apparently see this as giving a built-in safety element—which is totally fallacious. Their trust should be placed in tested medications, not those that are relatively untested. We talked a little about DTC advertising. You both believe to be, in general, a positive thing. It appears to reassure the patient that these medications are generally used and are safe. You have talked about the problem of mentioning adverse effects without being able to also give probabilities of benefit versus harm. Have studies been done to determine whether that discussion dissuades patients from long-term adherence? Dr. Jacobson: I am not aware of formal studies in the lipid field that assesses the optimal way to frame to patients the benefits of statin therapy versus the actual risks. In my mind, the number needed to treat with statins for clinical benefit is vastly superior to the number needed to harm due to side effects. Unfortunately, DTC ads have heightened public perception that these drugs can cause significant liver injury. Here we have a very safe and effective medicine with a side effect that no one believes is really detrimental and it’s deterring patients from taking it. I think we need to be very proactive as members of the NLA in taking on this issue. However, in a surprise turnabout, the FDA announced in February 2012 that they have revised the labeling for statins and have removed the need for routine periodic LFT monitoring during statin therapy. The

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labels now recommend that LFTs should be obtained before starting statin therapy and then later when clinically indicated. Although this is a good first step in perhaps allaying some of the public’s concerns about liver side effects, more educational efforts will be needed to further overcome this perception. Dr. Brown: The one clearly documented adverse effect of statins is rhabdomyolysis. Fortunately this is a very uncommon occurrence, and most physicians will never see a case. Also, I believe that reducing even this rare effect is possible. By warning a patient to remind other physicians who are writing a new prescription that they are taking a statin. Simply asking if this new prescription might interfere with the statin can help avoid a significant reason for statin toxicity. Dr. Jacobson: Patients need to be personally concerned about drug interactions and for good reason. We are an aging society that is actually living longer, has more chronic diseases, and is taking multiple medications. Fortunately, at the pharmacy level or even at the level of e-prescribing, a patient or provider may now be told, ‘‘You can’t use this antibiotic with this statin,’’ and so there’s a greater awareness. Unfortunately, many clinicians are still unaware of some of the relative common drug interactions with statins, which may increase a patient’s risk of side effects, particularly those of myalgia and myopathy. However, clinicians need to also consider the big picture for patients in trying to help them stay compliant despite changes in formulary coverage, co-pays, or the use of potentially interacting medications. As a recent example is the change in simvastatin labeling to no longer use the 80-mg dose. I have many patients who have been on 80 mg of simvastatin along with calcium blockers for many years without a problem and now our electronic medical record is saying, ‘‘Take them all off.’’ I think this strategy is wrong because many patients have been on these regimens for many years without side effects and half the battle is maintaining long-term compliance. Thus, although I may no longer initiate therapy with 80 mg of simvastatin in my practice, I’m not going to stop it in all patients who have been on it for several years and are otherwise doing well. In some patients they may have already failed three other statins and this would be clearly losing ground. So at times I think you have to be reasonable and use clinical judgment and common sense when interpreting new changes in recommendations. Dr. Brown: In this FDA statement there was a warning about starting with the 80-mg dose. If the patient has successfully taken it for a year, there’s no reason to discontinue it. I agree, I think that should hold for all medical regimens. The one problem is that adding a drug that competes in uptake or catabolism of the statin by the liver, the statin can build up to levels toxic to muscle. This can be an additive effect by two or three medications with different competing pathways in drug clearance. It’s something we all need to consider. Dr. Jacobson: I agree that providers need to better understand the drug interactions with statins and the

11 conditions that predispose to increased risk of rhabdomyolysis such as hypothyroidism, chronic renal disease, diabetes, and polypharmacy. One point which we haven’t covered yet is cost. In the recent Statin USAGE Survey (Understanding Statin Use in America and Gaps in Education), we found that although side effects were the major reason for discontinuing statin therapy, cost was then the next most common reason cited. In addition among current statin users, cost was the main reason for switching statins, and frequent statin switching was linked to lower rates of adherence. I think the issue of cost won’t go away soon even with low-priced generics. There still remain issues of formulary coverage, managed care contracting, and widespread statin switching leading to discontinuation and nonadherence. I think practitioners need to be aware of the cost sensitivity of their patients and make appropriate recommendations based on that. Similar to asking about adherence, if you do not ask about cost as a barrier, you will never know the cost sensitivity of patients. Although the advent of the $4 WalMart pharmacy has made a big difference, it still only covers the lower-potency statins. Whether the newest statin to enter the generic category, atorvastatin, will be added to the low price statins in formularies such as Walmart is not yet known. I think that we also have to appreciate that patients are also taking other drugs that are also very expensive. In addition, many often are too embarrassed to tell us that they can’t afford their medicines or are not taking them as directed so they can last longer. Often when you look at what else they’re taking, you will see many feel-good drugs that have nothing to do with altering disease activity. I have nothing against drugs like Viagra, but Viagra— Dr. Braun: Is expensive! Dr. Jacobson: We have to talk to patients about cost and find out if that’s their chief barrier to compliance. If so, let’s consider generics, 90-day supplies, tablet splitting, patient assistance plans, or other alternatives. I would say that even insurance companies should start to consider lower co-pays for chronic disease medications like statins since they are very cost-effective. They not only reduce mortality and morbidity, but they reduce the need for expensive revascularization procedures. It might even be advantageous to give then out for free to high-risk groups such as those with cardiovascular disease or diabetes. As practitioners, we can’t just put our head in the sand and ignore cost as a barrier to compliance and better outcomes. Dr. Braun: This goes back to the notion of the patient/ provider, or patient/clinic relationship because we and our staff need to feel comfortable providing that kind of information. That’s why we as providers need to talk to our patients upfront about cost and to say, ‘‘For these reasons, I’m choosing to give you a nongeneric medicine; however, if this is a problem, if it’s not on your formulary, if you can’t afford it, I want you to call me.’’ Dr. Brown: I agree that this is very important. You need to ask them specifically about their formulary, which of the

12 available statins would cost least over time. I think that’s a great place to start. All are safe but effectiveness in a given patient is highly variable. You may need to change to a more potent drug but often the first drug produces a satisfactory result. Dr. Jacobson: I’m sure, Dr. Brown, even at the VA where the cost for many patients is not an issue, still adherence is part of a multifactorial problem. I would like to see institutions move more directly in addressing adherence by first monitoring it. I mean by looking, within closed systems like the VA or Kaiser and identifying those who are not taking their medicines. Patients could then be brought back to assess the problem, determine the potential barriers to compliance, and problem solve with new solutions. Is it a side effect or some other barrier? Providers need to be proactive about assessing adherence and intervening if barriers are present. There is too much passivity on the provider’s part, ‘‘We told the patient, they’re not doing it, it’s their problem.’’ But it actually is our problem, and more importantly it’s society’s problem. We all will end up paying more for it if people don’t take evidence-based medicines that are cost-effective. Dr. Braun: The one thing that we did not talk about that may impact adherence is what I call the transition time: the gap that occurs between hospitalization and resuming outpatient care. The assumption is that a patient is taking all of the medicines that you prescribed before hospitalization, and you learn that is not necessarily the case. Or maybe this is a new patient to you, someone you are seeing for the first time after they were hospitalized. It’s happened to me a number of times when I’ve seen a patient posthospitalization and he or she is not taking the medication that they were taking prehospitalization. Potentially the statin was discontinued in the hospital. Therefore, it’s very important to assess and reconcile medications. It might be helpful to use your nonphysician providers in your offices or your nursing staff to help assess medications. I’ve often picked up the phone to call the patient’s pharmacy to find out when was the last time prescriptions were filled. If the patient seems to be unsure, he didn’t bring all of his medicines with him, he didn’t bring a list with him, I have called the pharmacy. I have reviewed every single medicine with the pharmacy to see when it was refilled last and have found out the statin was last refilled a month before that hospitalization. This is really a safety issue because if you have a lipid panel back and that LDL is not at goal, and you increase the statin or change the medicine without having assessed if the patient actually has the medicine and is taking it, that’s a concern. Dr. Brown: Certainly it is possible that after a procedure by a cardiologist or a surgeon, the patient may be somewhat confused about the purpose of various medications. They get their orientation to the therapeutic regimen reset after the procedure and chronic medications may not be reincorporated into their therapy. I would like to make one other point from long experience. When a patient experiences chronic pain and blames the

Journal of Clinical Lipidology, Vol 7, No 1, February 2013 statin for the pain, the physician should not accept that diagnosis without evaluating other potential sources of the pain. Many times, when you start evaluating the pain, you find the real source and it is almost never the statin. A careful history and a neurological examination is the minimum. This is a very serious matter because chronic pain is a major reason given for discontinuing statin therapy. Dr. Jacobson: The leading side effect that patients experience with statins is probably myalgias. In general I think that most myalgias are fairly benign but providers fear the worst possible scenario of muscle damage leading to rhabdomyolysis. Fortunately, this is very rare occurring with the frequency of one out of 50,000 patients. Myalgias are estimated to occur in about 5 to 10% of the population on statins. The recent PRIMO study suggested that the rates of myalgia might be even higher ranging from 10% to 15% in patients on high-dose statins. We recently completed the Statin USAGE study and found the rate of myalgias to be 29% among 10,100 statin users. This is considerably greater than previous studies but very much in line with clinician’s experiences. So, unfortunately, in our lipid clinic, one-third of the patients referred to us are for statin intolerance. However, many of them are not truly statin intolerant and in our hands we can get about 90% of those referred to us back on a statin one way or another. So it is important, as Dr. Brown has suggested, to investigate other possible sources of patients complaints about pain. Many practitioners don’t take the time to investigate a patient’s complaint of myalgia and will generally just keep switching statins without properly documenting the nature of the patient’s muscle side effects. That is generally not the right approach. With this common side effect—we need to talk to patients proactively about it, and explain that it is often benign or related to exercise and rarely progresses to rhabdomyolysis. One of the reason we don’t get a baseline creatine phosphokinase (CPK) on everyone is they’re all often abnormal and so we only get a CPK when patients have significant muscle aches and pains that cannot readily be explained by increased physical activity or other conditions. I think we need better communication with patients about this. Dr. Brown: I take a different approach. I like to get CPK at baseline, before starting statins. Many have elevated values that are characteristic of that patient and are not pathologic. This is particularly true in patients of African ancestry and in large muscular men. The upper limit may be stated as 200 international units, but you may find that a given patient has values of four, five, even 800 IU. The problem is if you measure it later when you are trying to evaluate aches and pain and it’s an 800, you’re trapped, you’re going to have to stop the drug. Dr. Jacobson: That makes sense and we often get a baseline CPK in patients at greater risk of myopathy, such as those with hypothyroidism, chronic kidney disease, transplants, those with polypharmacy, and those on medicines that have known drug interactions with statins.

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Dr. Brown: We need better tests for evaluating pain of a chronic or intermittent nature, and we need to avoid simply accepting the patient’s diagnosis of the statin as the causative element. I want to thank Drs. Braun and Jacobson for joining me to discuss this extremely important problem of adherence to regimens, which can prevent cardiovascular disease. This is an area that concerns every physician, nurse practitioner, and health professional involved in both general practice and specialty medicine. I am sure that clinical lipidologists will find useful information in this discussion of their experience, insights and knowledge.

Reading List 1. Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding Statin Use in America and Gaps in Patient Education (USAGE): an Internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012;6:208–215. 2. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO Study. Cardiovasc Drugs Ther. 2005;19: 403–414. 3. Jacobson TA. Toward ‘‘pain-free’’ statin prescribing: a clinical algorithm for diagnosis and management of myalgias. Mayo Clin Proc. 2008;83:687–700.

13 4. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations by the NLA Statin Safety Task Force. Am J Cardiol. 2006;97:89C–94C. 5. Miller NH, Hill M, Kottke T, Ockene IS. The multilevel compliance challenge: recommendations for a call to action. Circulation. 1997; 95:1085–1090. 6. Aggarwal B, Mosca L. Lifestyle and psychosocial risk factors predict non-adherence to medication. Ann Behav Med. 2010;40: 228–233. 7. Allen JK, Dennison-Himmelfarb CR, Szanton SL, et al. Community Outreach and Cardiovascular Health (COACH) Trial. A randomized, controlled trial of nurse practitioner/community health worker cardiovascular disease risk reduction in urban community health centers. Circ Cardiovasc Qual Outcomes. 2011;4:595–602. 8. Artinian NT, Fletcher GF, Mozaffarian D, et al. Interventions to promote physical activity and dietary lifestyle changes for cardiovascular risk factor reduction in adults: a scientific statement from the American Heart Association. Circulation. 2010;122:406–441. 9. Berra K. Does nurse case management improve implementation of guidelines for cardiovascular disease risk reduction? J Cardiovasc Nurs. 2011;26:145–167. 10. Lewis LM, Askie P, Randleman S, Shelton-Dunston B. Medication adherence beliefs of community-dwelling hypertensive African Americans. J Cardiovasc Nurs. 2010;25:199–206. 11. Schedlbauer A, Schroeder K, Fahey T. How can adherence to lipidlowering medication be improved? A systematic review of randomized controlled trials. Fam Pract. 2007;24:380–387. 12. Touchette DR, Shapiro NL. Medication compliance, adherence, and persistence: current status of behavioral and educational interventions to improve outcomes. J Manag Care Pharm. 2008;14:S2–S10.