Is enough being done to tackle medication nonadherence?



Is enough being done
to tackle medication
nonadherence?

1. B. Afandi, United Arab Emirates
2. A. Almansari, Saudi Arabia
3. J. Boavida, Portugal
4. A. Chaib, Morocco
5. G. S. Stergiou, Greece
6. K. Tan Eng Kiat, Singapore
7. O. Yavuzgil, Turkey


1. B. Afandi, United Arab Emirates


Bachar AFANDI, MD, FACE
Tawam Hospital
Division of Endocrinology
Al Ain
UNITED ARAB EMIRATES
(email: bafandi@seha.ae)



Cardiovascular disease is the leading cause of death worldwide, accounting for 17.3 million deaths per year according to the American Heart Association and the American Stroke Association.1 Risk factors include smoking, physical inactivity, unhealthy diet, obesity, hyperlipidemia, hypertension, and diabetes. There is now enough evidence to state positively that lifestyle changes and treatments to lower blood pressure, low-density lipoprotein cholesterol, and blood glucose do reduce the risk of the development of and mortality from cardiovascular diseases. Proven effective treatments for the primary and secondary prevention of cardiovascular disease include, but is not limited to, lipid-lowering agents, angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin receptor blockers, β-blockers, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide- 1 receptor agonists, and antiplatelet therapy.2

However, despite the development of numerous guidelines by most health authorities to ensure a multifactorial management, adherence to therapy remains universally suboptimal. Nonadherence to lifestyle modifications and treatment plans is a global problem, which might be very significant in some cultures. Nonadherence to medications has been documented to occur in more than 60% of cardiovascular patients.3 The health consequences of nonadherence can be quite severe with multiple risks to patients and society alike. Nonadherence to medications causes increased comorbidities, complications, poor treatment, hospital admissions, poor health outcomes, death, medical care expenditures, and, most importantly, it causes a failure to respond to recognized effective treatments.4

Factors that affect adherence might be related to patients, physicians, and health care systems as a whole. Health illiteracy, language, cultural values, medical coverage, and socioeconomic status can all affect patients’ adherence to medical treatment. In this era of physician productivity, where time is of the essence, it is becoming extremely hard for physicians to have effective communications and build trust with their patients. Consequently, many physicians fail to achieve their obligations. On the other hand, patients have problems adhering to plans that they do not comprehend. Even highly educated and motivated patients have real problems with adhering to complex regimens.4-6 A recent audit of 572 patients with diabetes from our practice showed that only 33% of participants were rated as having a good knowledge of their illness.7 A second audit of 100 elderly women reported an illiteracy rate of 48%. One-half of the participants needed assistance understanding written medical information and one-third needed assistance on how to measure blood glucose. In addition, 43% reported the need for more medical information to manage their disease when they fast during the holy month of Ramadan. More than 60% of participants preferred the one-to-one medical teaching format.8

The health authorities must bridge the widening gap between the advances in pharmaceuticals and the development of strategies to promote patient adherence. The cornerstone must be endorsing empathic patient-physician partnerships with effective communication and social support from other health care professionals. Effective interventions for improving patient adherence must be individualized and tailored to the patients’ cultural backgrounds, specific conditions, and treatment protocols. Institutional programs to increase patients’ awareness about cardiovascular diseases are essential. The preventive mechanism of cardiovascular medications that do not necessarily relieve symptoms must be fully addressed to improve understanding and compliance. In order for patients to take responsibility, they must understand their medical conditions in their own words. They should be fully motivated to participate actively in the decision-making process to create their treatment plans.

Health care system investment in comprehensive patient education programs must parallel the huge investments made by pharmaceutical manufacturers. This investment is achievable and cost-effective, which will ultimately lead to better health care outcomes.


References
1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics— 2015 update: a report from the American Heart Association. Circulation. 2015;131(14):e29-e322.
2. American Diabetes Association. Standards of medical care. Diabetes Care. 2017; 40(suppl 1):S1-S135.
3. Baroletti S, Dell’Orfano H. Medication adherence in cardiovascular disease. Circulation. 2010;121(12):1455-1458.
4. Martin LR, Williams SL, Haskard KB, Dimatteo MR. The challenge of patient adherence. Ther Clin Risk Manag. 2005;1(3):189-199.
5. Gottlieb H. Medication nonadherence: finding solutions to a costly medical problem. Drug Benefit Trends. 2000;12(6):57-62.
6. Kravitz RL, Hays RD, Sherbourne CD, et al. Recall of recommendations and adherence to advice among patients with chronic medical conditions. Arch Intern Med. 1993;153(16):1869-1878.
7. Al-Maskari F, El-Sadig M, Al-Kaabi JM, Afandi B, Nagelkerke N, Yeatts KB. Knowledge, attitude and practices of diabetic patients in the United Arab Emirates. PLoS One. 2013;8(1):e52857.
8. Abuelmagd W, Afandi B, Håkonsen H, Khmidi S, Nair SC, Toverud EL. Health information needs of women with diabetes at a tertiary care hospital in United Arab Emirates. Presented at: Fourth Gulf AACE Chapter Annual Meeting, November 2016.

2. A. Almansari, Saudi Arabia


Abdulqawi ALMANSARI, MD
Dr Erfan and Bagedo Hospital
Jeddah
SAUDI ARABIA
(email: aalmansari@gmail.com)



“Adherence to long-term therapy for chronic illness in developed countries averages 50%. In developing countries, the rates are even lower. » WHO 20031

Lifelong treatment is essential for chronic illnesses, but poor adherence2 to lifestyle modifications and medical treatment is seen in a substantial number of cases in cardiometabolic diseases, especially in the diseases that do not involve pain or a change in quality of life, such as hypertension, dyslipidemia, and, to a lesser extent, uncomplicated type 2 diabetes. According to the International Diabetes Federation, in 2013 24% of the adult population (aged 20 to 79 years) in Saudi Arabia suffered from type 2 diabetes.3 In other words, one in every four adults was at risk of developing the catastrophic microvascular and macrovascular complications of this disease, calling for sound actions to be taken, including improving adherence to medications, which might not seem like a major issue from the point of view of some patients.

Although the introduction of once-a-day medications (eg, new angiotensin-converting enzyme inhibitors compared with captopril) has reduced the number of tablets patients have to take, adherence is still poor. Fortunately, this might improve if long-acting medications, such as medications taken annually or every 3 months, became available.

Patient education on the long-term complications of the disease, the benefits of adherence, and the effectiveness of the treatment creates a sophisticated patient who is able to weigh the risks and benefits of treatment adherence. Patient education should include the concept of the therapeutic action of medicines and show that nonadherence might lead to subtherapeutic doses.

The role of technology in the development of innovative methods for drug delivery is essential to overcome the problem of nonadherence. Continuous delivery systems, which can be implanted subcutaneously and release a drug over a long period of time in a calculated manner, would certainly improve treatment adherence, although they have not yet been tested clinically. Advanced delivery systems are required not only to manage the disease, but also to give patients the confidence that they are receiving their treatment in an optimal way, which will also be reflected on their psychology.

Therefore, increasing the effectiveness of adherence interventions may have a far greater impact on the health of a population than any improvement in specific medical treatments, and it is worthwhile spending time and energy on strategies to promote treatment adherence for cardiometabolic diseases.


References
1. World Health Organization. The world health report 2003. http://www.who.int/ whr/2003/en/whr03_en.pdf. Published 2003. Accessed September 18, 2017.
2. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353 (5):487-497.
3. International Diabetes Federation. IDF Diabetes Atlas, 6th ed. www.idf.org/diabetesatlas. Published 2013. Accessed September 18, 2017.

3. J. M. Boavida, Portugal


José Manuel BOAVIDA, MD
APDP, Associação Protectora dos
Diabéticos de Portugal
Lisboa
PORTUGAL
(email: jmboavida@apdp.pt)



According to the constitution of the World Health Organization,1 which was signed by the representatives of 61 states on July 22, 1946, “Health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity.” This statement can almost be a utopia due to the complexity of all the implied factors.

Science, technology, and knowledge have helped in the discovery and production of medications that are designed to fight chronic diseases, such as diabetes. These medications intend to decrease the cost to society of certain diseases by avoiding complications and increasing quality of life and access to them is being expanded to a wider population. However, people’s adherence to medication is far from desirable, with the outcomes being far from those expected.2 Diabetes and other cardiovascular diseases have a growing prevalence due to longer life expectancies and unhealthy lifestyle habits.

So, what is missing? Should science and society invest in new, more efficient (and cost-effective) medications to overcome the gap between what is happening and the initial objective? Should we try to understand why patients do not follow their prescription and what their doctors say? Why do people not do what they should, despite what they are told, and even after they recognize that they should do what they are told?

The complexity and specificity of each individual makes it impossible to reduce human beings into categories, such as diabetics or hemophiliacs, with a solution, eg, the prescribed medication. Instead, each person with diabetes is unique; therefore, they should be listened to, asked for their beliefs, and motivated to play an active role in the treatment of their disease.

Doctors still have an important role because they must contribute their biomedical knowledge and make decisions on which medication is more adequate to the specificities of the disease, but above all, which medication is more adequate to the specificities of the person with the disease. It is no longer sufficient to just analyze the symptoms with the view of getting a diagnosis and, consequently, prescribe a drug. The person with the disease should be considered as a variable in the equation, and is probably one of the most important variables since they can determine the success or the failure of the treatment.

In 2008, Jean-Philippe Assal3 defined therapeutic education as a tool designed to

“train patients in the skills of self-managing or adapting treatment to their particular chronic disease, and in coping processes and skills. It should also contribute to reducing the cost of long-term care to patients and to society. It is essential to the efficient self-management and to the quality of care of all long-term diseases or conditions, though acutely ill patients should not be excluded from its benefits. Therapeutic patient education is education managed by health care providers trained in the education of patients, and designed to enable a patient (or a group of patients and families) to manage the treatment of their condition and prevent avoidable complications, while maintaining or improving quality of life.”

The important conclusion is that, in addition to producing new medications, efforts should be made to spread and implement therapeutic patient education as a key concept in the self-management of chronic diseases to improve the quality of life.


References
1. World Health Organization. Consitution of WHO: principles. http://www.who.int/ about/mission/en. Published July 22, 1946. Accessed September 18, 2017.
2. Chin WW. A delicate balance—pharmaceutical innovation and access. N Engl J Med. 2015;373(19):1799-1801.
3. World Health Organization. Therapeutic patient education: continuing education programmes for health care providers in the field of prevention of chronic diseases. http://www.euro.who.int/__data/assets/pdf_file/0007/145294/E63674.pdf. Published 1998. Accessed September 18, 2017.

4. A. Chaib, Morocco


Ali CHAIB, MD
Service de Cardiologie
Hôpital Militaire Mohamed V
Rabat
MOROCCO
(email: alichaib@hotmail.com)



The prevalence of cardiometabolic diseases is steadily increasing worldwide. The long-term management of these diseases remains a challenge despite the many drugs used. The efficacy might be appreciated using some parameters (ie, blood pressure, glycemia, and lipidemia) that even the patients may follow. Cardiometabolic diseases usually involve a lifelong treatment, which eventually becomes difficult to adhere to, especially if the patient finds the results disappointing. At the same time, research and pharmaceutical industries continue to produce new drugs that promise to have a better impact on morbidity and mortality. However, the results obtained in real life by the new molecules are frequently below those obtained in randomized controlled trials.1

One of the causes for this difference in results is patients’ nonadherence to their long-term treatments. In fact, the most optimistic investigations evaluate treatment adherence to be less than 50%, with all that this involves, such as costs for medical consultations, disease aggravation, and repeated hospitalizations. The cost of nonadherence vs the production of new drugs should be assessed mainly in emergent countries, where the cost of treating cardiovascular disease and providing access to new drugs is a burden on public health. In the meantime, there are many ways to improve treatment adherence and these should be encouraged. Several proposals will make it possible to provide better and less costly treatments, such as a simplified educational message and the use of supports and diagrams that even an illiterate patient can understand.

As patients now have access to different mobile applications, it will be wiser to use smart devices (phones, tablets, etc) as reminder and surveillance tools that can simulate the strict monitoring of randomized controlled trials, which will improve treatment adherence.

Another way to motivate patients to be more adherent to their treatment will involve sensitizing and making them more responsible for their disease, the issues surrounding their treatment, and the assessment of the risks of cardiometabolic disease.2 Therefore, treatment adherence is not only a health issue, but also a budgetary one. Its improvement necessitates a broad mobilization of actors around targeted programs and specific objectives. The involvement of trained staff, not necessarily health care professionals, would be more advantageous and less expensive.

In return, the production of new drugs will certainly add value both for therapeutic efficacy and for reducing the morbidity and mortality of these chronic pathologies.3 However, there is no guarantee that adherence to these new products will be better than the old ones. Therefore, the production of new drugs will have to bring innovations that will ensure good treatment adherence, ie, once-daily dose regimens, fixed-dose combinations, or even new routes of administration. These innovations will certainly entail added cost, but it may be worthwhile if treatment adherence can be improved.3,4


References
1. Homedes N, Ugalde A. Clinical trials in Latin America: implications for the sustainability and safety of pharmaceutical markets and the wellbeing of research subjects. Salud Colect. 2016;12(3):317-345.
2. Lanhers C, Walther G, Chapier R, et al. Long-term cost reduction of routine medications following a residential programme combining physical activity and nutrition in the treatment of type 2 diabetes: a prospective cohort study. BMJ Open. 2017;7(4):e013763.
3. Shaw DL. Is open science the future of drug development? Yale J Biol Med. 2017;90(1):147-151.
4. Curtin F, Heritier S. The role of adaptive trial designs in drug development. Expert Rev Clin Pharmacol. 2017;10(7):727-736.

5. G. S. Stergiou, Greece


George S. STERGIOU, MD, FRCP
National and Kapodistrian University of Athens
Hypertension Centre, Third University
Department of Medicine
Sotiria Hospital, Athens
GREECE
(email: gstergi@med.uoa.gr)



In the management of cardiovascular risk factors, such as hypertension, hypercholesterolemia, and diabetes, there is considerable discrepancy in the control rates achieved in research trials and clinical practice. Recent long-term outcome trials showed that optimal control of hypertension is feasible in the vast majority of patients.1 In contrast, population studies in several developed countries showed that only about 50% of treated hypertensive patients achieved effective blood pressure control.2 These data suggest that human factors (doctor-patient cooperation), rather than treatment-related factors (lack of efficacy or adverse effects), are mostly responsible for the failure to control hypertension in clinical practice. Indeed, poor patient adherence with drug treatment is recognized as the number one reason for resistant hypertension.3 Poor treatment adherence results in incomplete control of hypertension, which leads to an increased risk of cardiovascular events and increased health care costs. Thus, for the vast majority of patients with uncontrolled hypertension, a more efficient application of the currently available drugs is needed rather than the development of new drugs.

To improve hypertension control rates, the scientific community needs to focus its attention and direct energy and resources into improving treatment adherence; however, this will require initiatives directed at both the patients and the doctors. Patient education is essential and requires time to be devoted by the doctor, particularly at the initial in-office visits when treatment decisions are made. Patients should understand the risks of elevated blood pressure, the principles of long-term drug therapy for hypertension, and the benefits of long-term treatment adherence and blood pressure control.

Recent trials have shown that combination therapy with three or more drugs is necessary to achieve optimal control in almost 50% of hypertensive patients with a high cardiovascular risk.1 Treatment simplification improves long-term adherence, which is feasible for most patients with hypertension with a single pill in the morning. One-, two-, or three-drug therapies are available as fixed-dose combinations, including renin-angiotensin- aldosterone system blockers (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), calcium channel blockers (amlodipine), and diuretics (hydrochlorothiazide or indapamide), which is the recommended triple therapy for hypertension.3 Add-on therapy with an aldosterone antagonist should be the fourth step for most patients, which can also be administered in the morning (two morning pills for the four-drug therapy), and it is expected to help achieve optimal blood pressure control in >80% of patients.3 If further blood pressure reduction is necessary, sympathetic nervous system blockers may be added (eg, β-blockers, α1-blockers, centrally acting antiadrenergic drugs), or the patients can be referred to a hypertension specialist.

Self-monitoring of blood pressure at home under medical supervision can get patients involved in their health management and improve treatment adherence and blood pressure control rates.4 Telemedicine techniques are also being used increasingly for long-term monitoring and will probably evolve as a 21st century solution because technology is advancing and becoming more user friendly and cheaper.5


References
1. Wright JT Jr, Williamson JD, Whelton PK, et al, SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116.
2. Kearney PM, Whelton M, Reynolds K, Whelton PK, He J. Worldwide prevalence of hypertension: a systematic review. J Hypertens. 2004;22(1):11-19.
3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension. J Hypertens. 2013;31(7):1281-1357.
4. Agarwal R, Bills JE, Hecht TJ, Light RP. Role of home blood pressure monitoring in overcoming therapeutic inertia and improving hypertension control: a systematic review and meta-analysis. Hypertension. 2011;57(1):29-38.
5. Omboni S, Gazzola T, Carabelli G, Parati G. Clinical usefulness and cost effectiveness of home blood pressure telemonitoring: meta-analysis of randomized controlled studies. J Hypertens. 2013;31(3):455-467.

6. K. Tan Eng Kiat, Singapore


Kevin TAN ENG KIAT, MBBS, MRCP, FRCP,
FAMS
Kevin Tan Clinic for Diabetes, Thyroid &
Hormones Pte Ltd
Mount Elizabeth Medical Centre
Singapore
SINGAPORE
(email: dr@ktclinic.com)



Cardiometabolic disease is a broad term encompassing cardiovascular disease and its metabolic risk factors. Over time, this term has expanded to include the spectrum of glucose intolerance, hypertension, atherogenic dyslipidemia, nonalcoholic fatty liver disease, polycystic ovarian syndrome, insulin resistance, visceral fat, impaired fibrinolysis (increased plasminogen activator inhibitor-1 and fibrinogen), and inflammation (increased C-reactive protein). The last decade has seen an explosion in the development of new molecules in this field, arguably mostly for diabetes. While the hope is that the development is moving in the “right” direction to produce better and more effective therapies, some of the issues are the higher costs and hence accessibility to the new therapies, and how compliant the patient is in adhering to the therapy.

Medication adherence or nonadherence is a complex matter that is influenced by physician-, patient-, and medication-related factors. Physician-related factors include the ability to communicate and motivate patients to enhance the concordance of views between doctors and patients, individualization of therapy and targets, and minimizing dosing complexities. Then, there are a whole host of patient-related factors, including concordant or disconcordant views with their doctor; attitudes toward Western medications and the disease that may be influenced by friends and family, media, previous experiences, and cultural beliefs; economic status; and remembering to take their medication. Finally, commonly known medication-related factors that influence compliance include cost, side effects, efficacy, ease of dosing, method of administration, and pill size.

We have to admit that inherent to the development of new therapies has been an improvement in efficacy, reduction in side effects, and ease of administration and dosing regimens. This also applies to existing therapies. The following list contains a few examples of these improvements:
◆ Incretin-based therapies in diabetes introduced a decade ago addressed the concerns of the efficacy of lowering blood glucose being accompanied by weight gain and hypoglycemia.
◆ The oral dipeptidyl peptidase-4 inhibitor agents have almost zero side effects, and they lower blood glucose with a weight neutrality and hypoglycemia that is comparable with placebo.
◆ For greater efficacy and weight reduction, there are injectable glucagon-like peptide-1 analogs. These should be compared best with insulin, the historic injectable therapy for diabetes. They provide blood glucose–lowering efficacy without the weight gain and hypoglycemia of insulin therapy and indeed with the advantage of weight loss. There is no titration of blood glucose required; the administration has moved from once/twice daily to once weekly, and, now, potentially to once every 6 months or longer. The devices that deliver glucagon-like peptide-1 analogs have also become simpler to use.
◆ The orally administered sodium-glucose cotransporter 2 inhibitors are an alternative for the efficacy of blood glucose– lowering with weight reduction and minimal hypoglycemia with additional benefits on lowering blood pressure, uric acid, and triglycerides.

If these options are not enough, fixed-dose, single-pill combinations further enhance compliance by reducing pill load and simplifying dosing regimens, for example, moving from the twice-daily dipeptidyl peptidase-4 inhibitor/metformin immediate release preparations to the once-daily dipeptidyl peptidase- 4 inhibitor/metformin XR preparations, with a similar move for the sodium-glucose cotransporter 2 inhibitor/metformin preparations. In most cases, there is also a cost-saving benefit with the fixed-dose, single-pill combinations. Gliclazide is a second generation sulphonylurea introduced in the 1970s, reformulated into a modified-release preparation (Diamicron MR 30 mg) in the early 2000s with better compliance as a once-daily administered pill and with lower hypoglycemia, and then, a decade later, introduced as its current MR 60 mg preparation to further enhance patient compliance at its most efficacious dosing. In conclusion, it is reassuring that we can see, in the last decade, the introduction of new therapies combined with measures to improve treatment adherence to the new and existing therapies.

7. O. Yavuzgil, Turkey


Oğuz YAVUZGIL, MD
Department of Cardiology
EGE University Medical School
Boronova, Izmir
TURKEY
(email: oguzyavuzgil@gmail.com)



As the elderly population is gradually increasing, coping with chronic illnesses has become increasingly complex. The challenge against both cardiovascular disease and its cardiometabolic precursors should have a comprehensive medical perspective covering many fundamental factors.

In the US, where almost 800 000 cardiovascular deaths occur annually, the rate of death due to “age-related heart disease (per 100 000 population) declined from 412 in the 1980s to 191 in 2012. Stroke, which was the third or fourth leading cause of death in the last 50 years, dropped to fifth place.1” Lifestyle and behavior changes undoubtedly had an effect on these positive changes. However, it is generally accepted that medicines that have effects on cardiovascular mortality are the most important contributors to this development. There are about 200 new medicines under development for cardiovascular disease and stroke, with clinical trials conducted and reviewed by the US Food and Drug Administration.1 Although it is not difficult to predict that these new agents, which are currently being developed in the treatment of many chronic diseases, such as atherothrombosis, lipid disorders, heart failure, and hypertension, will further reduce cardiovascular mortality rates in the future, it is not entirely clear whether randomized trial data actually reflects real-life data for all disease subgroups.

Suboptimal drug adherence appears to be the most important barrier between real life data and randomized study outcomes, which has also been described by the World Health Organization as a serious problem worldwide.2 Even in developed countries, it is known that almost one in two patients do not show adequate adherence to long-term treatments, which leads to worsening of the disease at the population level, an increased mortality rate, and serious financial loss in the long term.2 Statins, antihypertensives, and antithrombotics, which have a particularly wide primary and secondary area of use, are of the greatest interest in this subject area. In the Heart and Soul study, a study that is investigating the importance of self-reported adherence, cardiovascular events are twice more frequent in participants without good treatment adherence; this condition remains an independent risk factor for subsequent adverse cardiovascular events after adjustment for baseline features.3 A study showed that maintaining good adherence to statins for at least 2 years resulted in a 30% reduction in the risk of acute myocardial infarction; this result is even better than in patients receiving higher doses of statins.4 More striking scientific evidence for the importance of drug adherence came from the CHARM study (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity). In this study, the risk reduction resulting from good treatment adherence was more prominent than the benefit obtained with the study drug.5

In summary, given the magnitude of the problems with drug adherence, it appears that the drugs that are currently available to treat cardiovascular diseases are not used with sufficient levels of adherence. Therefore, ensuring that the available drugs are used with appropriate adherence in the general population is perhaps more important than the development of new agents, and may in fact bring positive effects faster.


References
1. Medicines in development for heart disease and stroke: a report on cardiovascular disease. http://www.phrma.org/report/medicines-in-development-for-heartdisease- and-stroke-20151. Published December 8, 2015. Accessed September 18, 2017.
2. World Health Organization. Adherence to long-term therapies: evidence for action. Geneva. http://apps.who.int/medicinedocs/en/d/Js4883e. Published 2003. Accessed September 18, 2017.
3. Gehi AK, Ali S, Na B, Whooley MA. Self-reported medication adherence and cardiovascular events in patients with stable coronary heart disease: the heart and soul study. Arch Intern Med. 2007;167(16):1798-1803.
4. Penning-van Beest FJ, Termorshuizen F, Goettsch WG, Klungel OH, Kastelein JJ, Herings RM. Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study. Eur Heart J. 2007;28(2):154-159.
5. Granger BB, Swedberg K, Ekman I, et al; CHARM Investigators. Adherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial. Lancet. 2005;366 (9502):2005-2011.