Medication Adherence: Critical to Achieving the Triple Aim

While much has been written about the changing landscape of the American healthcare system, particularly the drive to achieve better health outcomes at lower cost, less attention has been paid to the contribution that basic scientific research makes toward achieving these goals. This is especially true in the case of chronic illness where there have recently been some notable advances in treatment options, especially those involving drug therapies. Better management and treatment of chronic illness will be a key driver in reducing costs given that 75% of the nation’s expenditure for healthcare goes toward caring for the chronically ill.[1]

In its 2012 National Health Interview Survey of Americans, the CDC found that more than 12% of respondents reported that they were limited in their routine activities because of one or more chronic conditions, i.e., more than 40million Americans live daily with the deleterious impact of chronic illness.[2] Disturbingly, the same survey found that more than 1/3 of Americans under the age of 65 who had health insurance – either private coverage or through Medicaid – either delayed or declined medical care due to the expected cost of that care.[3] For people living with chronic conditions, delaying or foregoing medical care can have severe adverse health consequences; chronic illness is the leading cause of death in the US.[4] For the American healthcare system, not managing chronic illnesses can have severe adverse financial consequences; when patients do finally arrive at the provider’s door they are generally sicker and more costly to treat than they would have been had their conditions been managed effectively over time.[5]

For those Americans who have been diagnosed with a chronic illness, adhering to their medical treatment plan is key to managing their condition and preventing, or postponing, additional complications. While treatment will necessarily involve multiple approaches, care plans commonly include the long-term use of prescription medications.[6] Failure to take medications as prescribed has very real negative consequences to both the health of patient and the health of the US health care system.[7] In just the cases of diabetes and heart disease, research has shown that patients who did not adhere to their medication plans had statistically significant higher mortality rates when compared with patients who took their medications as prescribed.[8]

The CDC estimates that between 20%-30% of prescriptions are never filled and that 50% of patients do not continue to use their medications as prescribed, e.g., they skip doses or simply stop taking them.[9] Analysis of rates of adherence across some of the more common chronic conditions have found that patients generally followed their medication plan for the first three months but after six months there was a consistent decline in adherence.[10]

Recent estimates put the cost to the US healthcare system of drug non-adherence at between $100-$289billion annually, representing 3% – 10% of total annual costs – costs that were avoidable.[11] These estimated costs of non-adherence do not include the price that the American economy and society pay for poor, or no, management of chronic illness – reduced productivity, increased absenteeism, and a higher frequency of disability, a price that has been estimated to be more than twice the “direct” costs of healthcare in the US.[12]

While non-adherence rates vary across disease types, there are well-recognized factors that influence whether a patient will adhere to a medication plan.[13] These factors include the patients themselves — the degree to which they are health literate, the extent to which they have been included in developing the care plan, and their mental and physical capacity to follow the regimen. Providers also influence adherence – the efficacy of their communication with patients and the number of prescribing providers. Adherence also depends on the structure of the healthcare system – the ability of patients to access their provider, having sufficient appointment time for effective patient-provider communication, and the availability of HIT to both the patient and provider.

Included in the range of factors that influence adherence is the medication regiment itself – the number of medications prescribed, the number of daily doses required, whether the therapy interferes with a patient’s lifestyle, the extent and severity of side effects, and the length of time that the patient must stay on the regimen.[14] Research has shown that, on balance, it is more important that patients finish their treatment than that they precisely adhere to the dosage intervals.[15]

Addressing the issue of non-adherence involves all participants in the healthcare system – including those entities engaged in basic science that are searching for drug therapies that are easier to follow and easier to tolerate. The need for better alternatives to extant therapies is well demonstrated by the case of chronic liver disease, specifically hepatitis C virus (HCV).

HCV is a chronic liver disease that is associated with liver failure, liver cancer and cirrhosis but which, with proper treatment, can be cured in a large number of cases.[16] [17] It is the most common chronic blood borne infection in the US; estimates are that 3.2million Americans have the virus and that millions more are infected but are undiagnosed as the symptoms often are not obvious until the disease has progressed significantly.[18] The CDC estimates that if every baby boomer were tested for HCV, an additional 800,000 cases would be found.[19] Left untreated, the disease will progress to end stage liver disease, the only effective treatment for which is a transplant that can cost upwards of $500,000.[20]

While HCV is curable in many instances, the drug therapies, which can take from six to twelve months to complete, have been shown to be effective but can have side effects that are sufficiently severe as to deter, or prevent, many patients from completing the course of treatment.[21] [22] The side effects of current drug therapies are sufficiently problematic as to warrant the Department of Veteran Affairs having a webpage devoted to coping with them (www.hepatitis.va.gov). Listed on the VA’s website are the following side effects: fever/chills, muscle and body aches, headaches, fatigue, depression, anxiety and irritability, insomnia, dry mouth or mouth ulcers, bad taste in mouth, poor appetite, nausea and vomiting, diarrhea, dehydration, cough, dry skin or a rash, hair loss or thinning, anal-rectal discomfort, and injection site reactions.[23] Other side effects of current drug therapies include low white or red blood count and low platelet count.[24]

But the pipeline of research into alternatives to current therapies is beginning to mature; several new drugs have recently won FDA approval and others are in line to be approved soon. These new drugs have fewer side effects than do older drugs, can be tolerated by a wider range of patients, and offer a shorter treatment length – increasing the likelihood of better adherence and a better health outcomes.

In November 2013, the FDA approved for use in adults Janssen Pharmaceutical’s Olysio (simeprevir), a protease inhibitor that blocks a specific protein that is needed by the hepatitis C virus in order to replicate.[25] This new drug was evaluated in combination with two drugs currently in use, peginterferon-alfa and ribavirin; when Olysio was added to the regimen, results showed significant increases in the numbers of clinical study participants who showed a sustained virologic response at least twelve weeks after completing treatment, i.e., hepatitis C was not detected in their blood.[26] Side effects include itching, rashes, nausea, muscle pain, and indigestion.[27]

Less than two weeks later, the FDA approved another new drug to treat chronic hepatitis C – Gilead Pharmaceutical’s Sovaldi (sofosbuvir), a nucleotide analog inhibitor that also blocks a specific protein that is needed by the virus to replicate.[28] Sovaldi was shown in trials to be effective against different strains of the virus in combination with both peginterferon-alfa and ribavirin or with just ribavirin. For patients who cannot tolerate an interferon-based treatment, e.g., those with liver cancer or those awaiting a transplant, this new treatment option is a significant advance.[29] In addition, Sovaldi showed fewer side effects than did other options, the most common being fatigue, headache, nausea, anemia and insomnia. Sovaldi was approved under the FDA’s priority review program for drugs that offer the potential for significant improvements in safety and effectiveness in the treatment of serious or life-threatening conditions.[30]

And on October 10, 2014, Gilead Sciences, Inc. obtained FDA approval for the first stand-alone drug therapy for hepatitis-C.[31] This new drug, Harvoni, combines a new agent with Sovaldi into one pill that is to be taken once a day for between eight and twelve weeks depending upon how for the infection has progressed. Gilead estimates that the approximately 35% to 40% of patients whose disease has not progressed far enough to scar their liver will be able to take the shorter, eight week, course of treatment. In clinical trials, Harvoni cured a slightly higher percentage of patients than did regimens that included Sovaldi.[32] Harvoni obviates the need for the injections that are still part of treatment that uses Sovaldi and which can cause depression, depression and headaches. Harvoni addresses the important issues of patient adherence and side effects that so frequently can derail the efficacy of hepatitis-C treatment.

Olysio and Sovaldi immediately came onto the US market; by mid-2014 more than 70,000 Americans had been treated with Sovaldi despite what some consider to be its high cost ($84,000 for a 12-week, once-a-day regimen).[33] For the approximately one-third of patients who can be treated with Harvoni for just eight weeks, the price will be approximately one-third lower than that of Gilead’s Sovaldi; the shorter course will cost $63,000.[34] The full twelve-week course will cost $94,500.[35]

There are many promising new pathways that are in the late stages of development and approval. In February 2014, the FDA granted Breakthrough Therapy Designation to Bristol-Myers Squibb’s investigational daclatasvir dual regimen (daclatasvir + asunaprevir) for treatment of one of HCV’s genotypes for use as a combination therapy. This new option offers hope for patients who either cannot tolerate or are not candidates for interferon or who have not responded to interferon-based regimens.[36] In June 2014, AbbVie, Inc. announced that the FDA had granted priority review to its new, interferon-free, multi-pill treatment; the review period is rapidly approaching its six-month deadline. [37]

There is substantial research that shows that the long term costs to the US healthcare system of poor health outcomes for Americans with chronic illnesses far exceeds the cost of the medications required to treat those illnesses.[38] Innovative scientific research that can lead to better management of, and in cases such as HCV cures for, chronic illnesses, will save the US healthcare system significant costs over the long term. In the case of innovative drug therapies, finding regimens that improve patient adherence to treatment plans – by simplifying the plan, by reducing side effects, by shortening the duration of the treatment – will accelerate the pace at which America achieves its goal of better health outcomes at lower cost.

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[1] https://www.cdc.gov/chronicdisease/index.htm

[2] https://www.cdc.gov/nchs/data/series/sr_10/sr10_259.pdf (page 13 & 14)

[3] https://www.cdc.gov/nchs/data/series/sr_10/sr10_259.pdf (page 35)

[4] https://cmcd.sph.umich.edu/what-is-chronic-disease.html

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934668/

[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068890/

[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934668/

[8] https://www.biomedcentral.com/1471-2261/6/48

[9] https://www.cdc.gov/primarycare/materials/medication/docs/medication-adherence-01ccd.pdf

[10] https://www.ncbi.nlm.nih.gov/pubmed/19954264

[11] https://www.cdc.gov/primarycare/materials/medication/docs/medication-adherence-01ccd.pdf