You should always do what your doctor is telling you, it’s a must. That is what we are persistently told. Medication compliance (sometimes referred to as “medication adherence”) normally is defined as “the degree to which a patient correctly follows medical advice” [1]. It is considered to be one of the fundamental requirements for the effective treatment especially for patients with a long term chronic disease. Medical community is more or less unanimous in labelling non-compliance as a major obstacle to the effective delivery of healthcare. Nevertheless, according to many respectable sources like WHO and Mayo Clinic “although medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed” [2]. The statement presupposes that medications are effective no matter who and why is to take them.

The team of researchers from the University Hospital of Leicester came to a quantitative conclusion through an experimental test of compliance. A total of 40 most commonly prescribed antihypertensive medications (or their metabolites) were screened for in spot urine samples to test patients’ compliance. After conducting a research among 208 hypertensive patients (125 new referrals, 66 follow-up patients with inadequate blood pressure control and 17 renal denervation referrals) who underwent assessment of antihypertensive drug intake using high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis at the time of clinical appointment the team came to the sad conclusion: “Overall, 25% of patients were totally or partially non-adherent to antihypertensive treatment (total non-adherence 10.1%, partial non-adherence 14.9%)” [3].

The damage of non-compliance is measured not only in medical terms, but also in terms of material losses that the healthcare industry has to bear. Thus the WHO shares the results of the studies which point that “the poor adherence to medication leads to increased morbidity and death and is estimated to incur costs of approximately $100 billion per year” [5]. The National Health Service (NHS) UK estimates the costs of medication treatment for patients with coronary heart disease (CHD) in excess of £2 billion on medicines, 50% of which is wasted through poor understanding and poor adherence [6].

But why 50% of patients even though suffering from acute chronic diseases such as CHD or, e.g., cerebrovascular accident (CVA) are consciously ignoring their doctors’ prescriptions?

Many highly regarded medical publications would name multiple reasons including a “poor communication between physicians and patients”, “lack of patients involvement in the decision process”, “patient illiteracy and lack of understanding of medication benefits and side effects”…

To avoid scholarly discussions, but as a care giver to patients with both CHD and CVA, I came to the firm conclusion: the main reason that patients do not take their medications is because those medications simply do not work for them, at least the patients fail to notice tangible improvements and have to rely on the doctors’ assertions.

For several years, I have been observing a patient with high blood pressure, cardio-vascular problems and diabetes mellitus on top of its all. The traditional medication treatment was a combination of ACE inhibitor or angiotensin-converting enzyme inhibitor (in this case Ramipril), calcium channel blocker (e.g., Lercanidipin or similar preparates) and beta-blockers (e.g., Bisoprolol).

Having taken Ramipril for 2 week the patient started complaining of unpleasant chest pains (presumably heart vessels reacted) and sleep problems. The physician’s response was unconditional and definite: “it is not possible. These side effects are atypical for Ramipril. There may be only slight cough.” Only due to the patient’s persistency, Ramipril was substituted by Valzartan, an angiotensin II receptor antagonist, more commonly called an ARB. The effect of Valsartan and Lercanidipin combination unfortunately had no effect on the reduction of the blood pressure and apparently did not help with CHD. Recently, I came across an article published in Jama Networks (thanks to the Internet and social networks!) “Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality, Cardiovascular Deaths, and Cardiovascular Events in Patients With Diabetes Mellitus: ”[7].The authors, Jun Cheng, MD, of the Medical School of Zhejiang University, China and his colleagues compared the effect of two types of medication on patients with cardio-vascular diseases and diabetes mellitus: ACE inhibitors and ARB. The conclusion was that “Angiotensin-converting enzyme inhibitors reduced all-cause mortality, CV mortality, and major CV events in patients with DM, whereas ARBs had no benefits on these outcomes. Thus, ACE-Is should be considered as first-line therapy to limit excess mortality and morbidity in this population.” For my patient, it meant that the swallowed Valsartan had probably no effect on his CHD.

Bisoprolol reduces the activity of the heart by blocking tiny areas (called beta-adrenergic receptors) where the messages are received by the heart muscle. This could provoke a bradicardia – one of the many possible side effects of this medication. We simply had to drop bisaprorol to recover the normal pulse rhythmus.

Almost all medications aimed at treating people with long term chronic conditions have severe side effects that are revealed gradually and tend to accumulate in the body.Cold sweats, fainting, fast or irregular heartbeat, nausea, shortness of breath to mention just a few are numbered as the “typical” side effects of antihypertensive medications.

But what about the ones we are buying in our nearby drug stores? Even less sophisticated widely available drugs such as ibuprofen or even aspirin could cause unpredictable side effects in certain individuals.

Jason Ryan, 28, from Washington, near Sunderland, suffered a severe allergic reaction which is believed to have been sparked by taking the over-the-counter drug ibuprofen and turned into Stevens Johnson Syndrome (SJS), which causes the skin cells to die before shedding [8].

If 50 percent of patients are not taking their prescribed medications, there is definitely something fundamentally wrong with the way our healthcare and pharmaceutical systems are working. For centuries, the traditional healthcare system was addressing a “typical” patient with a “standard” reaction on medications. This approach appears to be methodologically wrong since it is based on an implicit assumption of the universal validity of the Gauss distribution underlying medical statistics. Yet the statistics of emergent diseases, similarly to heavy accident statistics, seem to obey other distribution laws such as, e.g., power law distributions rather than sharply dropping exponential ones that imply negligible stray areas.

Unfortunately, the statistical results, e.g. produced in clinical trials, in fact do not answer the crucial question: what is the best strategy for a given patient. The variations of human organisms are much more complex and diverse to bring them under the unified umbrella of a statistically average person. This is pretty much the same as to measure “an average temperature” of all patients in a hospital – even accurately computed standard deviations would leave many “stray” patients outside of the main massive. But it is these latter patients that have to be dealt with sometimes taking much more doctors’ time than the average ones. Someone is crouching in fever, while somebody had already peacefully passed away. The average temperature though is normal.

The so-called “personalized devices” (both hardware and software) such as smart pill bottles or health feedbacks systems that are now coming out on the market are predominantly focused on reminding a patient to take prescribed medications vs. contemplating what medication a given individual requires at the current instant. Similarly, personal portals that allow patients getting a direct access to their physicians do not completely solve personal health issues: doctors will be still restricted by numerous health protocols as well as by health insurance plans. The latter will not allow to cover the variety of medications outside of their agreements with certain hospitals and/or pharmaceutical companies.

Certain hope lies on personalized approach to medications based on preemptive genotyping (PG). Thus, the Mayo Clinic initiated a study “Right Drug, Right Dose, Right Time” using genomic data of Mayo Clinic biobank participants, with a recruitment goal of 1000 patients connected to their electronic medical records (EMR). The multivariate prediction model was applied to identify patients with a high risk of hyperlipidemia requiring treatment with statins within three years. The model included 6 chronic diseases categorized by the Clinical Classifications Software for International Classification of Diseases, the Ninth Revision codes (dyslipidemia, diabetes, peripheral atherosclerosis, disease of the blood-forming organs, coronary atherosclerosis and other heart diseases, and hypertension). The Mayo Clinic researchers hope that clinical implementation of PG at the bedside could make it possible to avoid adverse drug reactions, maximize drug efficacy, and select medications to optimize effect for specific indications on the basis of the genetic profile of individual patients [9].

Of course such endeavors would require time and money. But can’t it be more efficient to invest $100 billion per year in the therapy that brings the result helping people to survive than totally wasting the money?

References:

1. http://en.wikipedia.org/wiki/Medication_compliance
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068890/
3. http://heart.bmj.com/content/early/2014/02/20/heartjnl-2013-305063.abstract?sid=fec46ffa-3bce-41d1-a0ed-139e235620ae
4. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353(5):487-497. [PubMed]
5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068890/#R3
6. http://en.wikipedia.org/wiki/Medication_compliance
7. https://archinte.jamanetwork.com/article.aspx?articleid=1847572
8. http://www.dailymail.co.uk/health/article-2542083/Father-left-coma-skin-peeling-taking-ibuprofen-flu.html
9. http://www.mayoclinicproceedings.org/article/S0025-6196(13)00929-4/fulltext