Drug-Drug Interactions and Their Association With Quality of Life in Patients With Hypertension

Introduction This study aimed to evaluate drug-drug interactions (DDIs) and their association with the quality of life in patients with hypertension. Materials and methods This cross-sectional study included 123 patients with hypertension. DDIs were evaluated using the Medscape Drug Interaction Checker Database (Medscape, New York, NY). The EuroQol-5D (EQ-5D) Quality of Life Scale was used for each patient. Results The overall blood pressure control rate (systolic/diastolic blood pressure levels, <140/90 mmHg) was 43% (53/123). The age of the patients with uncontrolled hypertension was higher than the patients with controlled hypertension (63.67 ± 11.00 vs. 58.42 ± 10.07 years; p = 0.007). The number of DDIs showed significant correlations, positively with age (r = 0.303, p = 0.001), total number of drugs (r = 0.784, p < 0.001), number of antihypertensive drugs (r = 0.640, p < 0.001), and body mass index (BMI) (r = 0.321, p < 0.001) and inversely with EQ-5D index score (r = −0.247, p = 0.006). The EQ-5D index and visual analog score were inversely correlated with age and BMI. Additional significant linear correlations between age and the total number of drugs, age and number of the antihypertensive drugs, the number of antihypertensive drugs and BMI, and the number of total drugs and BMI were detected. Of a total of 511 identified DDIs, 14 interactions in 12 patients were considered serious, 402 interactions in 82 patients were considered significant, and 95 interactions in 39 patients were considered minor. Conclusions This study supports that DDIs have important associations with antihypertensive treatment and the quality of life of patients. Higher age and BMI values were associated with a higher risk of DDIs and lower quality of life in patients with hypertension.


Introduction
Hypertension is the most known early-onset form of cardiovascular disease, and insufficient blood pressure control is a global public health challenge and is associated with cardiovascular mortality and morbidity [1].In contrast to this well-known influence, the success rate of the treatment in patients with hypertension is not at a satisfactory level [2].Therefore, enhancement of the success of antihypertensive treatment is the main target globally [3].The treatment of hypertension, especially in patients with markedly high baseline blood pressure levels, is required to initiate combinations of antihypertensive drugs to achieve target blood pressure levels [4].On the other hand, concomitant treatments related to the high prevalence of diabetes mellitus, dyslipidemia, and other chronic diseases are very frequently encountered in patients with hypertension [5].There are two major concerns regarding drug-drug interactions (DDIs) potentially caused in the treatment of hypertension.First, the DDIs can cause an alteration of the therapeutic effect of antihypertensive treatment.The second is based on safety concerns that DDIs can increase the risk of unexpected adverse reactions to either or both drugs.
In the case of any condition that requires multiple drug treatments, the management of DDIs is a critical challenge faced by physicians in daily practice.In addition to the lack of awareness, the rapidly increasing

Evaluation of quality of life
The EuroQol-5D (EQ-5D) Quality of Life Scale [7], consisting of five questions, and a visual analog scale (VAS) was used.The EQ-5D index score and VAS score were evaluated separately.The EQ-5D index score was calculated using the answers given by the patients to the three-option (no problems, moderate problems, and extreme problems) questions, and the "index calculator" was used as recommended in the guideline of the scale.For the EQ-VAS score, the patients were requested to mark a value on the ruler-like scale after being informed that "0" indicated the worst possible health level and "100" was the best possible health level.Before starting the study, permission to use the scale was obtained from the EuroQol Group Foundation.

Statistical analysis
Statistical analyses were conducted using IBM SPSS Statistics, version 21.0 (IBM Corp., Armonk, NY).The Shapiro-Wilk test was used for evaluating the distribution of variables.T-test and Pearson's correlation analyses were used for variables with normal distribution.The Mann-Whitney U test and Spearman's rho correlation analysis were used for variables without normal distribution.The results are presented as mean ± standard deviation (SD) and median (25th-75th percentiles).The p-values of <0.05 were considered statistically significant.

The differences between patients having controlled and uncontrolled
In addition to significantly higher SBP and DBP in the uncontrolled group, the age of the patients with uncontrolled blood pressure was higher than those with controlled blood pressure (63.67 ± 11.00 vs. 58.42± 10.07 years; p = 0.007).The number of DDIs and number of received antihypertensive medications were higher in the uncontrolled group; however, the differences did not reach a statistically significant level (for the number of DDIs, controlled vs. uncontrolled: 3.25 ± 4.19 vs. 4.86 ± 5.21, p = 0.067; for the number of received antihypertensive medications, controlled vs. uncontrolled: 2.13 ± 0.94 vs. 2.44 ± 0.97, p = 0.067).
BMI (kg/m 2 ), pulse rate/min, the total number of drugs, EQ5D index scores, and EQ scale scores did not differ between the controlled and uncontrolled groups.The differences between the controlled and uncontrolled groups are presented in Tables 1, 2.

Correlations between study parameters
There was a significant linear correlation between age and SBP (r = 0.324, p < 0.001) and an inverse correlation between DBP and age (r = −0.208,p = 0.021).The number of DDIs showed significant correlations, positively with age (r = 0.303, p = 0.001), the total number of drugs (r = 0.784, p < 0.001), the number of antihypertensive drugs (r = 0.640, p < 0.001), and BMI (r = 0.321, p < 0.001) and inversely with EQ-5D index scores (r = −0.247,p = 0.006).On the other hand, the EQ-5D index score was inversely correlated with age (r = −0.199,p = 0.027), the number of total drugs (r = −0.230,p = 0.011), and BMI (r = −0.324,p < 0.001).Also, the EQ-5D VAS score was inversely correlated with age (r = −0.176,p = 0.051) and BMI (r = −0.343,p < 0.001).There were additional significant correlations between age and the total number of drugs (r = 0.431, p < 0.001), age and the number of antihypertensive drugs (r = 0.215, p = 0.017), the number of antihypertensive drugs and BMI (r = 0.239, p = 0.008), and the total number of drugs and BMI (r = 0.271, p = 0.002).As expected, there was also a strong correlation between the number of antihypertensive drugs and the total number of drugs (r = 0.614, p < 0.001).The correlations between study parameters are given in

Evaluation of drug-drug interactions
At least one DDI was identified in 67.5% (83/123) of the study population.Of these, 21.7% (18/83) had only DDIs between antihypertensive drugs, and the vast majority were not remarkable in daily practice.In the present study, 511 DDIs were detected using the Medscape Drug Interaction Checker.Of these, 14 interactions in 12 patients were considered serious (use an alternative medication), 402 interactions in 82 patients were considered significant (monitor closely), and 95 interactions in 39 patients were considered minor.Additionally, among all identified 511 DDIs, 168 were between antihypertensive drugs.Hypertensive patients with diabetes mellitus had a higher number of significant DDIs (z = −3.778,p < 0.001), minor DDIs (z = −5.186,p < 0.001), and total number of DDIs (z = −4.493,p < 0.001) than hypertensive patients without diabetes mellitus.The number of serious DDIs did not differ between the patients with and without diabetes mellitus.Hypertensive patients with dyslipidemia had a higher number of significant (z = −3.343,p = 0.001), minor (z = −2.062,p = 0.039), and total number of DDIs (z = −3.564,p < 0.001) than the hypertensive patients without dyslipidemia.However, the number of serious DDIs did not differ between the patients with and without dyslipidemia.All serious DDIs are given in Table 4. Additionally, the 10 most common drug pairs that showed significant and minor interactions are presented in Tables 5, 6, respectively.

Drug pairs Frequency Mechanism of interaction Recommendation
Aspirin-ramipril 4

Discussion
Hypertension is one of the most common chronic diseases and the most important preventable risk factor for cardiovascular diseases.According to the results of the TEKHARF study published in 2017, it was estimated that hypertension affected approximately 6 million male and 8 million female patients in Turkey [8].
The association of hypertension with increasing age is well known.The increased prevalence of the disease is also related to the increasing aging population [9].The management and control of hypertension in the geriatric population need close monitoring and intensive follow-up.One of the main reasons for insufficient control of hypertension in older patients can be related to the comorbid conditions that need additional medications.It is a fact that polypharmacy can reduce compliance with medication, especially in the geriatric population [10].In addition to the possible direct effects of comorbid conditions and related medications on blood pressure levels, polypharmacy may also lead to certain DDIs with antihypertensive drugs and decrease or increase the effect and/or adverse effects of antihypertensive treatment.In our study, it was demonstrated that the age of the patients with uncontrolled blood pressure was significantly higher than that of those with controlled blood pressure.Additionally, we found significant correlations between age and the total number of prescribed drugs, the number of antihypertensive drugs, drug interactions, and EQ-5D index scores.It can be concluded that age by itself is related to a higher incidence of uncontrolled hypertension and has an association with the need for multiple medications, thus increasing the risk of DDIs, which may contribute to a decrease in the quality of life of patients.
Our data were also consistent with the findings of a recent study that highlighted the association of increasing age and polypharmacy with DDIs in patients with hypertension [11].In the present study, age also correlated positively with SBP and inversely with DBP.This finding may support previous knowledge that a wider pulse pressure level is an additional important risk factor for cardiovascular diseases in older patients [12].On the other hand, the number of DDIs and the number of prescribed antihypertensive drugs tended to be higher in the uncontrolled group, though the difference did not reach a significant level, possibly due to the small sample size.
Obesity is an important public health challenge, and the increased prevalence in recent years carries a great risk for the development of hypertension and cardiovascular diseases [13].In our study, the BMI score was positively correlated with the total number of prescribed drugs (r = 0.239, p = 0.008), the number of antihypertensive drugs (r = 0.271, p = 0.002), and DDIs (r = 0.321, p < 0.001).This finding may suggest that the patients with higher BMI scores have a higher number of comorbid conditions and use multiple drug treatments, thus leading to a drug interaction risk.The quality of life was also inversely correlated with BMI values, evidenced by both EQ-5D index scores (r = −0.324,p < 0.001) and EQ-5D VAS scores (r = −0.343,p < 0.001).These findings support that high BMI scores are one of the major risk factors contributing to the quality of life and management of antihypertensive treatment.Therefore, awareness should be increased globally, and patients should be informed to avoid possible complications of obesity and DDIs.
The most common comorbid conditions were diabetes mellitus and dyslipidemia among the study participants.The direct effect of both diseases on blood pressure levels could not be compared because the sample size and population of the study were not appropriate for this evaluation.The higher prevalence of hypertension among patients with diabetes and/or dyslipidemia [14,15] should be taken into consideration, and their effects on blood pressure levels should not be ignored.As an expected result, the presence of both conditions increased the risk of DDIs, including significant and minor interactions.However, the number of serious drug interactions did not significantly differ between the groups.The incidence of serious drug interaction was very low in the entire study population due to the small sample size and the data from a specialized clinical pharmacology polyclinic.Therefore, the risk of serious DDIs in subgroups should be evaluated in further studies surrounding larger populations.
One of the aims of the study was to identify the drug pairs that interact with each other and to determine the severity and mechanism of the DDIs in patients with hypertension.According to the Medscape Drug Interaction Checker Database, the possible recommendations were extracted and interpreted.In a previous study that aimed to evaluate the antihypertensive drug interactions for nine months after baseline, it was reported that approximately 75% of the patients had at least one interaction at baseline, and the number of interactions increased over time [16].In our study, 67.4% (83/123) of the patients had at least one drug interaction that was compatible with the existing literature.The results of our study and previous knowledge support that DDIs should be taken into consideration for the successful management of antihypertensive treatment.Even in our relatively small study population, a remarkable number of 14 serious, 402 significant, and 95 minor interactions were detected.Only two of these 14 serious interactions did not involve antihypertensive medications.It is a fact that the vast majority of serious DDIs can be considered avoidable.
The interaction between simvastatin and calcium channel blockers can be given as an example.In this case, replacement of treatments with appropriate alternatives, such as the use of a different statin not metabolized through the CYP3A4 pathway or changing the antihypertensive treatment regimen, can reduce the risk of serious complications such as rhabdomyolysis.
The vast majority of the DDIs fell under the category of significant interactions (monitor closely).Most common five drug pairs that showed a significant interaction were valsartan-aspirin, valsartanhydrochlorothiazide, atorvastatin-valsartan, carvedilol-valsartan, and hydrochlorothiazide-metoprolol.Pharmacodynamic interactions between antihypertensive drugs were not remarkable for daily practice because the synergy between the blood pressure lowering effects of antihypertensives is a natural outcome, and it does not indicate that these drugs should not be used concomitantly.It is well-known that, as mentioned before, guideline recommendations for patients with markedly high initial blood pressure levels are to initiate treatment with an appropriate combination of antihypertensive drugs.However, other significant interactions require close monitoring, such as serum potassium levels with concomitant use of carvedilol and valsartan or valsartan-hydrochlorothiazide, and if possible, stopping or replacing the concomitant treatment, or modifying treatment with concomitant use of hydrochlorothiazide and metoprolol to protect patients from eye/vision-related complications.
Our results indicated that the interactions between aspirin and renin-angiotensin-aldosterone system (RAAS) blockers required special emphasis because both are widely used in patients with cardiovascular disease, and their interactions may be overlooked in daily practice.Even in our relatively small sample size, there were four serious, 61 significant, and two minor interactions between aspirin and other cardiovascular drugs.The serious interaction between aspirin and ramipril, an angiotensin-converting enzyme (ACE) inhibitor, is based on the possible risk of a decrease in renal function, and additional interaction is caused by non-steroidal anti-inflammatory drugs (NSAIDs) inhibiting vasodilating renal prostaglandins, thus disrupting the blood pressure lowering effects of ACE inhibitors.The other significant (monitored closely) interaction between these drugs is based on impaired renal functions, especially in the elderly and patients with volume depletion, according to the Medscape Drug Interaction Database.
Although there are no serious interactions between aspirin and valsartan (the most commonly used angiotensin-receptor blocker [ARB] in the study), there are significant interactions that require close monitoring.The mechanism of significant interactions between aspirin and valsartan is very similar to the interaction of ramipril with aspirin; however, the severity level is not the same.The mechanism and severity of the DDIs of aspirin with other ACE inhibitors (including perindopril, lisinopril, and trandolapril) and ARBs (including candesartan, losartan, and telmisartan) were the same.With the high risk of drug interaction of aspirin with antihypertensive drugs, the patients should first be evaluated for an aspirin indication.The proven benefit of aspirin in the secondary prevention of cardiovascular diseases is well established; however, the effect of aspirin in the primary prevention of cardiovascular diseases is not clear due to a poorly defined balance of benefit and bleeding risk.Accordingly, the recommendations and guidelines on the use of aspirin in primary prevention are very restricted [17].Therefore, the concomitant use of aspirin in the treatment of patients with hypertension should be carefully evaluated because both RAAS blockers and aspirin are cornerstone medications in the treatment of several atherosclerotic cardiovascular diseases.
In other cardiovascular conditions, such as heart failure, however, the concomitant use of aspirin and ACE inhibitors is debatable.It was stated in a previous publication that the risk of drug interactions between aspirin and ACE inhibitors could be associated with the severity of heart failure; therefore, avoiding the use of aspirin and other NSAIDs, and if needed, the use of other antiplatelet agents not disrupting the prostaglandin synthesis, such as clopidogrel, might be considered in patients with severe heart failure [18].
In general, we recommend that if aspirin is clearly indicated and needs to be used with a RAAS blocker, use of a low-dose aspirin range of 75-100 mg (in line with guidelines' recommendation [17]), selection of ARBs without serious interaction with aspirin, and maintaining close monitoring of renal functions may be a better approach until new evidence comes into view.
The results of our study demonstrated that DDIs were related to decreased quality of life.Both the EQ-5D index and VAS scores tended to demonstrate an inverse correlation with the number of DDIs, but only the correlation of the EQ-5D index score (r = −0.247,p = 0.006) reached significance.However, this may be enough for a clinical evaluation because VAS scores are a more subjective assessment based only on patient consideration.In this sense, this finding revealed that the successful management of DDIs has the potential to improve the quality of life in patients with hypertension.

Limitations
The main limitation was the relatively small sample size of this single-center study.However, even in our relatively small study population, the remarkable number of DDIs detected showed the importance of the management of DDIs in patients with hypertension.On the other hand, this study has a cross-sectional design; therefore, the results provide only a snapshot of the current situation.It should be kept in mind that the present study demonstrates the correlations but not causation between study variables due to the study design and statistical analysis.According to the detected DDIs, appropriate alteration in treatment plans and their effects on blood pressure levels and quality of life should be evaluated further in future studies.

Conclusions
The results of the present study are important in highlighting the association of DDIs in the management of antihypertensive treatment and the quality of life of patients.Additionally, the increased need for multiple medications, increased risk of DDIs, and decreased quality of life were demonstrated in patients with older age and higher BMI scores.Among the detected DDIs, the interactions between aspirin and RAAS blockers required special emphasis.The need for aspirin use should be thoroughly considered in line with guideline recommendations.Regarding current knowledge, if aspirin is indicated and needs to be used with a RAAS blocker, the better approach may be to select an ARB without serious interaction with aspirin and maintain close monitoring of renal functions.

TABLE 1 : The differences in study parameters between the controlled and uncontrolled groups
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; EQ

TABLE 4 : Serious drug-drug interactions among prescribed drugs
2024 Gürel et al.Cureus 16(3): e56526.DOI 10.7759/cureus.56526Either increases the toxicity of the other by other.Aspirin decreases effects of valsartan by pharmacodynamic antagonism.Valsartan and aspirin both increase serum potassium.Use caution/monitor.Both may result in renal function deterioration, particularly in elderly or volume-depleted individuals.Modify therapy/monitor closely.NSAIDs decrease the synthesis of vasodilating renal prostaglandins and thus affect fluid homeostasis and may diminish the antihypertensive effect.Use caution/monitor.Risk of fetal compromise if given during pregnancy.Effect of interaction is not clear; use caution.Use caution/monitor.

TABLE 5 : The 10 most common drug pairs that showed significant interactions
Severity, mechanism, and recommendations were given according to the Medscape Drug Interaction Checker Database.NSAIDs, non-steroidal anti-inflammatory drugs; OATP1B1, organic anion transporting polypeptide 1B1 2024 Gürel et al.Cureus 16(3): e56526.DOI 10.7759/cureus.56526FrequencyMechanism of interaction RecommendationHydrochlorothiazidemetformin 32Hydrochlorothiazide will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance.Hydrochlorothiazide decreases effects of metformin by pharmacodynamic antagonism.Minor/significance unknown.Minor/significance unknown.Thiazide dosage of >50 mg/day may increase blood glucose.

TABLE 6 : The 10 most common drug pairs that showed minor interactions
Severity, mechanism, and recommendations were given according to the Medscape Drug Interaction Checker Database.OATP1B1, organic anion transporting polypeptide 1B1