Evaluation of potential drug- drug interactions among Palestinian hemodialysis patients

Chronic Kidney Disease (CKD) is a global public health concern [1]. End-stage renal disease (ESRD) and CKD are increasing worldwide [2, 3]. The variation among communities in the incidence of ESRD mirrors that in the prevalence of diabetes, obesity, and hypertension [4]. The prevalence of ESRD patients on dialysis in the West Bank, Palestine is comparable with that of adjacent countries, but is still far below the high prevalence rate recorded in Western countries [5].

Patients who go through ESRD and who receive hemodialysis (HD) are expected to be given 10 to 12 medications daily and many of these medications require multiple doses each day. Due to poly-pharmacy, frequent medication adjustments on dialysis versus non- dialysis days, medically unstable nature of the disease and restricted life styles, these patients are at high risk for developing drug related problems (DRPs) and non-adherence. With such a large number of medications, there is an increased risk for drug-drug interactions (DDIs) [6], which is associated with significant morbidity, impaired quality of life, mortality, and others such as primary drivers of hospital admissions and health care costs. The specialist must keep in mind that pharmaceutical options must be balanced with the potential risk of multiple medication use. The potential risks include, but are not limiting to, adverse effects, inappropriate dosing regimens, drug-disease interactions and drug-drug interactions [7].

Even though, DDIs are considered as preventable medication related problems, studies revealed that up to 11 % of patients experience symptoms associated with DDIs and these are responsible for approximately 2.8 % of hospital admissions [8]. It is important to remember that recognizing a potential DDI in a patient, does not mean he will suffer from an actual DDI and a clinically significant effect, sometimes extra monitoring is the only action needed. Monitoring of potential DDIs may improve the quality of prescribing and dispensing and it might form a basis for education focused on appropriate prescribing [9].

It is hoped that this study will help raise awareness of the importance of drug monitoring and review in hemodialysis patients. Help both clinicians and researchers to have a better view on this topic in terms of prevalence and risk factors and guide clinicians on how to avoid such interactions. If such interactions can be avoided this will increase the patients’ quality of life, survival and satisfaction.

The aims of this study are to find the prevalence and nature of potential drug-drug interactions (DDIs) in patients with Hemodialysis and identify factors associated with these interactions if present.

The patients in this study had many comorbidities. Hypertension, diabetes mellitus, gout, and myocardial infarction were the most common co-morbid conditions present in the HD patients respectively. Regarding the cause, there are many causes that can lead to the ESRD, for which HD should be initiated. A high number of HD patients in this study had hypertension as a cause of ESRD, followed by diabetes mellitus and polycystic kidney disease. In comparison with other studies, in a study from Thailand and another from Latin America, the most common cause of ESRD was diabetes mellitus [11, 12].

In this study, the 275 HD patients were prescribed 90 different drugs with a mean (± SD) of 7.87 ± 2.44. The number of medications in this study is close to a Japanese study where the mean was around 7.2 medications [13]. However, this result is lower than a study in Malaysia that included ESRD patients where the mean was around 9 medications [14]. Also, this is lower than a study from the USA where the mean of medications prescribed for HD patient reached 12.3 ± 0.5 medications [15]. In summary, polypharmacy is very common in ESRD patients.

The most commonly prescribed medications in current study were calcium carbonate, followed by alfacalcidol, iron/folic acid, aspirin and amlodipine. When compared with a study conducted at a nephrology unit in a Malaysian hospital, the top five used medications were calcium carbonate (which was the most commonly prescribed medication also), followed by a combination of folic acid and vitamin B complex, and the third commonly prescribed medication was metoprolol followed by lovastatin and ferrous sulfate [14]. Another cross-sectional, observational study was conducted in nephrology department of a government hospital in India, the five most commonly prescribed drugs were multivitamins, iron, folic acid, calcium carbonate, and calcitriol [16]. Due to this poly-pharmacy, HD patients are at higher risk for drug related problems including DDIs.

In the present study, we found that the prevalence of potential DDIs in medications of CKD patients was 89.1 %, this is a very high percentage. Another high prevalence was seen in a study from the India where the potential DDIs among renal failure patients reached 76.09 % [6]. When actual DDIs were evaluated in a study performed in U.S by Grabe et al., they accounted for 27.5 % of detected drug related problems [17].

There are different methods that can be used to identify and classify drug-drug interactions that have been used in different studies. In current study, LexiComp® was used for this purpose. Most of the potential DDIs were C-risk rating which means that monitoring is needed. In 78 potential DDIs detected, therapy modification was required according to the recommendations as their risk rating was D. In a prospective, observational study that was carried out in a South Indian tertiary care hospital, every combination of prescribed drug was analyzed using the Thomson Reuters Micromedex® DrugReax® system to look for potential DDIs, among the 156 patients, 474 potential drug interactions were identified. Most of them were delayed in onset, moderate in severity, pharmacodynamic in nature, and belong to level 2 i.e., moderate in significance [6]. This confirms that not in all cases of potential DDIs we need to stop the combination.

Univariate analysis showed that potential DDIs were affected by age, number of diseases and drugs. This is similar to a study from the USA which showed that older age and number of drugs prescribed were more likely to lead to major interactions [18]. It is recommended that more attention should be given to patients with chronic diseases as hypertension and diabetes, which are considered the most common co-morbidity among our HD patients, and that all their drugs should be documented and screened for potential DDIs.

Among different categories of drugs involved in potential DDIs, most of them were those of daily use to treat patients with chronic disorders. The most common potential interaction was calcium carbonate with amlodipine, followed by aspirin with calcium carbonate and then aspirin with furosemide, enoxaparin, and insulin. However, in another study performed by Rama et al. (2012), they found that beta blockers, calcium channel blockers, diuretics, digoxin and antiarrhythmic agents, were the most common medication involved in the list of potential DDIs. The most frequently prescribed drug combinations with potential DDI were ascorbicacid/cyanocobalamine, clonidine/metoprolol, amlodipine/metoprolol and insulin/metoprolol [6].

Physicians and pharmacists should be more aware of these potential interactions and they should collaborate to develop educational programs and improve patients’ counseling to avoid improper use of medications. Further researches and actual steps are required to optimize patient outcomes and minimize the prevalence of these interactions. It is important to remember that not all DDIs are harmful. Some of these combinations can be beneficial. Our recommendation is to give more attention for patient’s medication list before considering this combination as desirable or undesirable drug interaction.

The first limitation of this study is that the sampling method was convenient, that limits the ability to make broader generalizations from the results. Another limitation is that the honesty of patient to report non -prescribed drugs and other information was no guaranteed. However, this study is the first of its type in Palestine. These results can give a baseline data that can be useful in finding the prevalence of potential drug-drug interactions in patients with ESRD and identify factors associated with these interactions if present and in designing and implementing suitable interventions, educational programs and performing other related studies.

The prevalence of potential drug- drug interactions among hemodialysis patients is very common; they are highly expected and depend on the number of drugs taken by the patients which were used to treat co-morbid conditions. Many of these interactions are considered as preventable medication related problems, so screening for potential interactions and monitoring regularly should take place routinely before prescribing any medication to improve quality of prescribing and dispending.

CKD, Chronic Kidney Disease; DDIs, Drug-Drug Interactions; DRPs, Drug Related Problems; ESRD, End-Stage Renal Disease; HD, Hemodialysis