WeCreativez WhatsApp Support
Welcome! My name is Damaris I am online and ready to help you via WhatsApp chat. Let me know if you need my assistance.

Download this complete Project material titled; Cost Effectiveness Evaluation Of Antihypertensive Combination Therapies In University Of Nigeria Teaching Hospital Ituku Ozalla, Enugu with abstract, chapters 1-5, references, and questionnaire. Preview Abstract or chapter one below

  • Format: PDF and MS Word (DOC)
  • pages = 65



Background: Efficient use of the combinations recommended by Joint National Committee (JNC7) guideline can improve cost of achieving goal blood pressure in our environment.

Objective: The objective of this study was to evaluate the cost effectiveness of model 1 (2 antihypertensive drug combinations) and model 2 (more than 2 antihypertensive drug combinations) for effective control of blood pressure in Nigerian hypertensive patients.

Method: Retrospective data and analytical model were used to determine the cost effectiveness of the two treatment model for the control of blood pressure from the patient’s perspective. Hypertensive patients were categorized into stage 1, stage 2 and sample population as a whole. Data extracted from the patients folders were used to estimate the cost and extent of blood pressure control achieved by the two treatment models and was used to calculate the average cost effectiveness ratio (ACER). A Monte Carlo’s simulation which simulated 1000 iterations was used to calculate mean incremental cost effectiveness ratio (ICER), a probabilistic cost effectiveness which was presented on cost effectiveness acceptability curve (CEAC) and Net monetary benefit. Data was analyzed using SPSS version 16 and Microsoft excel.

Results: In a sample of 201 patients that had 500 encounters, percentage use of model 1 compared to model 2 was 59% vs 41%. (ACER) of model 1 treatment compared to model 2 treatment was (₦839 vs ₦2471), (₦1407 vs ₦4415), (₦919 vs ₦3244) for stage 1, stage 2 and the sample population as a whole. Mean ICER of model 1 over model 2 was ₦-3295, ₦-10935.2, ₦-2836.2 for stage 1, stage 2 and sample population as a whole. Probabilistic cost effectiveness of model 1 treatment was higher than model 2 treatment over most of the willingness to pay value. Average net monetary benefit of model 1 compared to model 2 was ₦2837 vs ₦1237, ₦1171 vs ₦154, ₦2400 vs ₦639 for stage 1, stage 2 and all patients respectively.

Conclusion: The study provides evidence that 2 antihypertensive drug combinations is more cost effective than more than 2 antihypertensive drug combinations in achieving target blood pressure for all stages of hypertension in Nigeria.














1.1 Background. 1

1.2 Statement of the problem.. 3

1.3 Significance of the study. 4

1.4 Definition of hypertension. 5

1.4.1 Previous definition and classification of hypertension in Nigeria. 5

1.4.2 New definitions and classification of hypertension. 8

1.5 Etiologies of hypertension. 12

1.5.1 Genetic consideration. 12

1.5.2 Primary hypertension. 12

1.5.3 Secondary hypertension. 12

1.6 Risk factors in hypertension. 13

1.7 Pathophysiology. 13

1.7.1 Pathogenesis of hypertension. 14

1.8 Complication of hypertension. 14

1.9 Management 15

1.9.1 Goals of management 15

1.9.2 Life style modification. 15

1.9.3 Pharmacological treatment 16

1.9.4 Managing hypertension with combination therapy. 17

1.10 Pharmacoeconomics. 20

1.11 Concept of pharmacoeconomics. 20

1.12 Methods of economic evaluation. 21

1.12.1 Cost Minimisation Analysis (CMA). 22

1.12.2 Cost effectiveness analysis (CEA). 22

1.12.3 Cost utility analysis (CUA). 24

1.12.4 Cost benefit analysis (CBA). 24

1.13 Types of pharmacoeconomic studies. 25

1.14 Cost analysis. 25

1.14.1 Categorizing cost 26

1.15 Consequences. 26

1.16 Why do we study pharmacoeconomics. 27

1.17 Review of previous study. 27

1.18 Objectives of the study. 32


2.1 Study design. 34

2.2 Study setting. 34

2.3 Study population. 35

2.3.1 Inclusion criteria. 35

2.3.2 Exclusion criteria. 35

2.4 Data collection. 35

2.5 Cost consideration. 36

2.6 Outcome consideration. 37

2.7 Economic evaluation. 37

2.8 Cost effectiveness acceptability curve. 38

2.9 Net monetary benefit 40

2.10 Ethical approval 40

2.11 Data analysis. 40


3.0 Folder selection. 44

3.1 Demographic data. 44

3.2 Clinical data. 47

3.3 Assessing the pattern of use of JNC 7 specification. 49

3.4 Treatment outcome. 52

3.5 Economic outcome. 55

3.6 Cost effectiveness analysis. 57

3.7 Products of simulations. 64

3.7.1 Cost Effectiveness Acceptability Curves (CEAC). 64

3.7.2 Net Monetary Benefit (NMB). 68


4.1 Discussion. 73

4.2 Limitations of study. 78

4.3 Recommendation. 79

4.4 Conclusion. 79

4.5 Contribution to knowledge. 79

Appendix 1: Comparison of costs of drugs used in the treatment models. 87

Appendix 2: Code for the visual basic macro to record simulation of incremental cost effectiveness ratio, acceptability curve and net monetary benefit. 89

Appendix 3: Ethical clearance. 90



1.1 Background

Hypertension is a prevalent disease and worldwide prevalence estimates for hypertension may be as much as 1 billion individuals, and approximately 7.1 million deaths per year may be attributed to hypertension (Chobanian, et al., 2003). It is the leading cause of congestive heart failure, chronic renal failure, cerebrovascular disease, of hospitalization, and of cardiovascular mortality and sudden cardiac death (Adigun et al., 2003). Beginning at blood pressure of 115/75 mmHg, cardiovascular disease (CVD) risk doubles for each increment of 20/10 mmHg. It has been identified as the third leading cause of Disability Adjusted Life Years (DALYS) and was estimated to be 64 million (DALYS) in 2002 (Ezzatti, et al., 2002). It is estimated that, by 2025, 29% of the adult world population will be hypertensive, which is approximately 1.56 billion people (Kearneyet al., 2005). Hypertension is a threat to the health of people in sub- Saharan Africa and a major contributor to morbidity and mortality in the sub-region (Ogah, 2012).


A systematic review done in Nigeria showed that the prevalence of hypertension is more in urban than rural area (Ogah, 2012). Due to propelling economic factors, most rural areas in Africa is changing into peri urban and urban areas (Opie & Mayosi, 2005) that translates to many developing hypertension. Kearney et al stated that by 2025, 75% of world hypertensive patient will be in developing country. This may be due to increased urbanization, changes in lifestyle and diet of people in Africa.


The relationship between BP and risk of (CVD) is continuous, consistent and independent of other risk factors. Clinical trials has shown that reducing blood pressure with antihypertensive treatment are accompanied by a reduction of hypertension related cardiovascular risk and overall mortality (Neal, et al., 2001; Pasty, et al., 1997; Black, et al., 2001). The need to attain goal blood pressure has led to development of many guidelines for management of hypertension most notably the guideline by the Joint National Committee on Prevention, Detection, Evaluation and treatment of High Blood Pressure (JNC7) (fig. 1.1). The guideline recommends a thiazide diuretic therapy as the initial pharmacologic agent for most patients with stage 1 hypertension, but was not strict on the option. It also stated that other class of drug or combinations of different drug class are appropriate choice for patients with stage 1 or stage 2 hypertension. The presence of “compelling indications” may also prompt treatment with antihypertensive agents that demonstrate a particular benefit in primary or secondary prevention resulting to use of combination therapy. Majority of patients with hypertension will require combination therapy to reach target blood pressure (Frank, 2008; Chobanian, et al., 2003; Unknown, 2010; Gradman, 2010).


World Development Indicators 2007, published by the World Bank, stated that more than 70% of Nigerians live on less than US $1 per day, impairing their ability to afford health care. In Nigeria there is a link between poverty, our socioeconomic status and hypertension (Adebisi & Samali, 2013). The control of BP among Nigeria hypertensive patients is still unacceptably poor despite the global awareness on hypertension. The reasons differ but scarcity and high cost of drug is most prevalent. A report by (Ekwunife, et al., 2010) stated that the proportion of hypertensive patients on treatment was 21% while 23.7% men and 17.5% women have their high BP treateed. The increasing burden of hypertension in Nigeria is likely to be of grave consequences because very few people get treated and the control is low. A Nigeria report, indicates that only 25.4% of patients attending a hypertensive clinic in a tertiary hospital achieved an optimum BP set at <140/90mmHg (Odili, et al., 2008).  This translates to a good number of hypertensive patients in Nigeria developing preventable complication of hypertension. With rising prevalence of hypertension and increasing cost of blood pressure control, Nigeria will experience economic and health challenges due to the disease. To improve treatment outcome in the management of hypertension, there is need to adopt a treatment strategy that will address the economic burden involved in treatment of hypertension. Economic evaluation will aid the provision of the most cost effective treatment strategy for hypertension and its complications in our scarce community. The need for economic evaluation in implementing treatment strategies to improve control of hypertension has also been identified by World Health Organization (WHO). One of the research priorities of hypertension in African countries as indicated by WHO is assessment of cost effectiveness of programs to detect and treat hypertension by improving awareness, treatment initiation and adherence, and level of control (WHO, 2008).

1.2 Statement of the problem

Hypertension is a major public health challenge and various studies have demonstrated that it is associated with high morbidity and mortality rates (Kiiskinen, et al., 1998; Dunn & Small 2001).

The cost of controlling blood pressure with antihypertensive agents is increasing and there is need to consider cost involved in achieving goal blood pressure in clinical practice.

Several studies have shown that patients are usually initiated and maintained on antihypertensive therapy with combination agents in Nigeria (Ukwe & Ubaka 2012; Adigun et al., 2003; Yusuf & Balogun 2005; Etuk, et al., 2008). This is attributed to late initiation of treatment, delayed diagnosis, inadequacy of pharmacological treatment (Yusuf & Balogun 2005; Ekwunife & Ubaka 2012; Ganiyu & Suleiman 2012). In many cases, combination therapy improves rates of blood pressure control and requires less time to achieve target blood pressure (Chobanian, et al., 2003; Bakris et al., 2007) with equivalent (Lacourcière et al., 2005) or better tolerability (Taylor,2004) than higher-dose monotherapy. Several studies have documented that black hypertensive patients are at increased risk of morbidity and mortality from cerebrovascular and cardiovascular event and will benefit from use of antihypertensive combinations (Douglas, et al., 2003; Kizer, et al., 2004; Drazner, 2004). Furthermore, black hypertensive patients have higher incidences of concurrent diseases such as left ventricular hypertrophy, congestive heart failure or congestive cardiac failure, diabetes mellitus and chronic renal failure and have been shown to benefit from use of anti-hypertensive drug combinations (Kazeem & Olumide 2005).

Despite the use of combination therapies specified by JNC 7 in the treatment of hypertension in Nigeria, cost effectiveness analysis on combination therapies is still scarce in Nigeria. Till date no study has analyzed the cost effectiveness of antihypertensive combinations recommended by various guidelines for management of hypertension in Nigeria. There is need for a comprehensive study on cost effectiveness of antihypertensive combinations recommended by JNC 7 which is largely used in University of Nigeria Teaching Hospital Ituku Ozalla.

1.3 Significance of the study

The treatment of hypertension is a continuous process which usually lasts for life. The economic consequence of this long term therapy is a key factor contributing to poor blood pressure (BP) control due to non adherence to prescribed antihypertensive medications.

The choice of combinations that will be more expensive, where more economical combination would be equally effective, may have negative impacts on individual budget. Application of limited health resources to the most cost effective intervention addresses health financing objective of efficiency.

Pharmacoeconomics study provides us with methodology to choose between two treatment options since resources are limited. This study has significance for the society, clinicians and patients.

Patients are always concerned about the cost of therapy prescribed and if they will derive value commensurate to the cost of the drug while doctors are concerned about affordable treatment to ensure compliance and complete recovery.

It will form basis for rational decision making in daily clinical practice and result in more efficient use of resources in health institutions as they will understand the antihypertensive agents to invest on.

Patient is part of the society, so this translates to society making more judicious use of their resources and deriving maximum value for price they pay for their drugs. This can improve compliance that is due to non affordability.

1.4 Definition of hypertension

Hypertension is defined as a disturbance in hemodynamic function in which there is a persistent abnormal elevation of systemic blood pressure whether systolic or diastolic, above the arbitrary level of normal pressure of 140/90 mm Hg (Chobanian, et al., 2003). It can also be defined as a condition where blood pressure is elevated to an extent that clinical benefit is obtained from blood pressure lowering (Dyker, 2012). Hypertension doubles the risk of cardiovascular disease including coronary heart disease (CHD), congestive heart failure (CHF), ischemic and hemorrhagic stroke, renal failure and peripheral arterial disease. Hypertension is present in all population except for a small number of individuals living in primitive culturally isolated societies and the prevalence of hypertension varies among countries and among subpopulation within a country (Fauci, et al., 2008). The risk associated with increasing blood pressure is continuous. Each 2 mmHg rise in systolic blood pressure is associated with a 7% increased risk of mortality from ischemic heart disease and a 10% increased risk of mortality from stroke. (NICE Guideline, 2011)


In 1996, a consensus group in Nigeria examined current hypertension guidelines from the United States (US), the United Kingdom (UK) and the World Health Organization/International Society of Hypertension (WHO/ISH) and was better informed to prepare a booklet which served as a useful guide to Health care practitioners treating hypertensive patients in Nigeria. The classification of blood pressure made for individual >15years of age is presented in table 1.1.                                         


Hypertension in adults (age 15 years and above) was then defined as a persistently elevated systolic blood pressure of more than 160 mm Hg and/ or diastolic pressure equal to or more than 95 mm Hg in the guideline (Nigeria Guideline, 1996). The group made the definition and classification bearing the socioeconomic factors in the country in mind. Probably they want to delay the initiation of antihypertensives since management is continuous throughout the individual’s lifetime or reduce the number of individuals with the stigma of hypertension.

(Standard treatment guideline  Nigeria, 2008) defined hypertension as a persistent elevation of the blood pressure above normal values (taken three times on at least two different occasions with intervals of at least 24 hours) Blood pressure ≥ 140/90 mmHg irrespective of age is regarded as hypertension.



Table 1:1 Classification of blood pressure by Nigeria guideline  

Normal <140 <90
Borderline 140-159 90-94
Stage 1 (MILD) 170-186 95-104
Stage 2 (MODERATE) 170-186 105-119
Stage 3 (SEVERE) = OR>190 = OR>120




A writing group in the American Society of Hypertension redefined and updated the classification of hypertension. It states that though blood pressure is an important biomarker of hypertension, the definition of hypertension cannot be based on blood pressure threshold alone as the elevated blood pressure is an effect and not the cause of hypertension. The new definition characterizes hypertension as a progressive cardiovascular syndrome that results in both functional and structural changes to the heart and vascular system progressing to damage to the heart, kidneys, brain, vasculature and other organs, often leading to premature morbidity and mortality (Giles, et al., 2009). The new definition incorporates the presence or absence of risk factors, early disease markers, and target-organ damage and more accurately represents the different physiological abnormalities in the cardiovascular system and other organs caused by hypertension. They noted that the early stages of hypertension can begin before the development of sustained high blood pressure. In their classification, an individual is normal or hypertensive, the staging of hypertension represents progression from early to advanced stage and is based on presence or absence of cardiovascular disease (CVD) and target organ damage (table 2).



Classification stage Normal Stage 1 hypertension Stage 2 hypertension Stage 3 hypertension
Descriptive category Normal blood pressure or rare blood pressure elevations and no identifiable cardiovascular disease Occasional or intermittent blood pressure elevations and early cardiovascular disease Sustained blood pressure elevations or progressive cardiovascular disease Marked and sustained blood pressure elevations or advanced cardiovascular disease
Cardiovascular risk factors None or few Several risk factors present Many risk factors present Many risk factors present
Early disease markers None Usually present Overtly present Over presently with progression
Target organ disease None None Early signs present Overtly present with or without CVD events




Table 1.2: Classification of hypertension by the WG ASH

Note: WG ASH Writing Group American Society of Hypertension

Interest is on cardiovascular status and is determined by constellation of cardiovascular risk factors, early disease marker and target organ damage.



Comparing various definition and classification of hypertension, the JNCVI and WHO/ISH used the same definition and classification.  The term prehypertension came up for the first time in JNC 7. Attention was brought to the blood pressure that was initially thought to be normal. In JNC 7 prehypertension is not a disease category and should not be started on antihypertensives without compelling indications. The idea is to initiate healthy life styles in these groups of individuals to delay or prevent cardiovascular disease with age.


The WG ASH definition identifies individuals that have vascular damage or early disease marker with a low BP as having stage 1 hypertension and requiring treatment while the individuals with rare blood pressure elevation and have no early markers of the disease are normal with the same risk of cardiovascular disease like the general population. It means that individuals with the same level of blood pressure might have different hypertensive status and some individuals classified as prehypertensive in JNC 7 might be normal by the ASH definition. The new definition of essential hypertension is intended to aid the clinician in identifying those individuals at high risk who need to undergo evaluation and treatment, as well as in selecting optimal treatment strategies for hypertensive patients with comorbid conditions and/or target organ damage.




Table 1.3: Comparison of JNC VI and 7, WG ASH and WHO ISH

Optimal Normal Normal Optimal <120 And <80
Prehypertension Normal or Hypertension stage 1 120-139 Or 80-89
Normal Normal 120-129 Or 80-84
Borderline High Normal 130-139 Or 85-89
Hypertension Hypertension
Stage 1 Stage 1 Stage 2 Grade 1 (mild) 140-159 Or 90-99
Stage 2 Stage 3 >or=160 Or >or=100
Stage 2 Grade2 (moderate) 160-179 Or >or=100
Stage 3 Grade 3 (severe) >or=180 Or >or=110


1.5 Etiologies of hypertension

Till date two etiologies of hypertension is known, the primary and secondary hypertension.


Hypertension represents a polygenic disorder in which a single gene or combination of genes act in concert with environmental exposures to contribute only a modest effect on blood pressure. Specific genetic variants have been identified in rare Mendelian forms of hypertension but these variants are not applicable to the vast majority (>98%) of patients with essential hypertension.


It is also known as the essential hypertension. Essential hypertension is a heterogeneous disorder, with different patients having different causal factors that lead to high BP (Carretero & Oparil, 2000). Elevated BP was wrongly perceived to be necessary for adequate perfusion of essential organs during the early and middle 1900s, it is now identified as one of the most significant risk factors for cardiovascular disease (Saseen & Carter, 2005). It tends to be familiar and is due to environmental factors interacting with genetic factor. It is the most common type of hypertension making up nearly 95% of all cases of hypertension. The exact etiology of essential hypertension is unknown (Koda Kimble, 2009) but this is only partially true because we have little information on genetic variations or genes that are overexpressed, underexpressed as well as the intermediary phenotypes that they regulate to cause high BP (Carretero & Oparil, 2000). Diagnosis of essential hypertension is made after all causes of secondary hypertension are excluded. This form of hypertension cannot be cured but can be controlled.



Secondary hypertension has specific identifiable cause and can be corrected if known. Secondary causes of hypertension include Chronic Kidney Disease, Chronic Steroid Therapy and Cushing’s Syndrome, Coarctation of the Aorta, Drug-Induced or Drug-related (adrenal steroids, alcohol in excess, amphetamines and anorexiants (e.g., phentermine, sibutramine), cocaine and other illicit drugs, Cyclosporine and tacrolimus, erythropoietin, Licorice (including some chewing tobacco) Nonsteroidal anti-inflammatory drugs and COX-2 inhibitors, oral contraceptives oral decongestants (e.g., pseudoephedrine), Some over-the-counter supplements (e.g., ephedra, bitter orange), pheochromocytoma, primary aldosteronism, Renovascular Disease, Sleep Apnea, Thyroid or Parathyroid Disease, (Koda Kimble, 2009).

1.6 Risk factors in hypertension

A number of risk factors are associated with hypertension and they are divided into two

The modifiable and non modifiable risk factors of hypertension

Modifiable risk factors include: obesity, smoking, alcohol intake, salt intake, physical activity, stress, environmental condition, certain chronic condition etc.

Non modifiable risk factors include age, gender, race and genetic factors.

1.7 Pathophysiology

A clear understanding of the regulation of atrial BP is needed to understand the management of hypertension. Atrial BP is interplay between blood flow and resistance to blood flow which is represented mathematically as product of cardiac output and total peripheral resistance in the following equation:

BP=CO X TPR…………………………Equation 1.1

A number of factors that are well understood have been associated with the regulation of blood pressure though the cause of essential hypertension is still unknown (koda kimble, 2009). Various neuronal and humoral factors are known to influence and regulate BP. These include the adrenergic nervous system (controls α- and β-receptors), the renin-angiotensin-aldosterone system (RAAS) (regulates systemic and renal blood flow), renal function and renal blood flow (influences fluid and electrolyte balance), several hormonal factors (adrenal cortical hormones, vasopressin, thyroid hormone, insulin), and the vascular endothelium (regulates release of nitric oxide, bradykinin, prostacyclin, endothelin) (koda kimble, 2009).


There are two main potential mechanisms for pathogenesis of hypertension. They include increased cardiac output: increased cardiac preload (increased fluid volume from excess sodium intake or renal sodium retention from reduced number of nephrons or decreased glomerular filtration); Venous constriction (excess stimulation of the RAAS and sympathetic nervous system over activity) and increased peripheral resistance: functional vascular constriction (excess stimulation of the RAAS, sympathetic nervous system over activity, genetic alterations of cell membranes and endothelial-derived factors); structural vascular hypertrophy (excess stimulation of the RAAS, sympathetic nervous system over activity, genetic alterations of cell membranes, endothelial-derived factors, hyperinsulinemia resulting from obesity or the metabolic syndrome) (Saseen & Carter, 2005).

1.8 Complication of hypertension

As hypertension progresses, various complication sets in. There is no specific level of BP where cardiovascular and renal complications start to occur (Carratero & Oparil 2000). The organs usually involved are the heart, kidney, eyes, brain and peripheral arteries. Pathological findings in these target organs show a worse prognosis compared to a hypertensive person with the same blood pressure but none of these findings. Organs that could be targeted include heart (Left ventricular hypertrophy, systolic or diastolic cardiac dysfunction, symptomatic heart failure, myocardial infarction, angina pectoris, ischemic heart disease or prior revascularization), brain (stroke, impaired cognition, dementia, encephalopathy), eyes (retinopathy), kidney (albuminuria (urinary albumin excretion >300 mg ⁄ d), chronic kidney disease (estimated GFR <60 mL⁄ min) or ESRD) and peripheral arteries (peripheral artery disease, aortic aneurysm)

1.9 Management

Since there is no specific symptom of hypertension attributable  to elevated high blood pressure, management usually include an initial assessment of complete history and physical examination to confirm a diagnosis of hypertension, screening for other cardiovascular disease risk factors, screening for secondary causes of hypertension, identifying cardiovascular consequences of hypertension and other comorbidities, assessing blood pressure–related lifestyles, and determining the potential for intervention (Fauci, et al., 2008).

Diagnosis of hypertension is usually made with average of two or more accurately seated measured BP on one or more occasion. The stage of the hypertension is determined and decision for treatment is made.

The treatment of hypertension involves combination of lifestyle modification and pharmacotherapy.


The end goal of treating hypertension is to reduce associated morbidity and mortality. Morbidity usually manifest as hypertension-associated complications. The surrogate goal of treating hypertension is to achieve goal BP values. Patients with hypertension have a BP goal of either <140/90, <130/80, or <120/80 mmHg. Patients with estimated 10-year risk of Coronary Artery Disease (CAD) of <10%, based on Framingham scoring, have a goal BP of <140/90 mmHg. Patients with chronic kidney disease and diabetes, have a goal BP of <130/80 mmHg. If patients have a history of left ventricular dysfunction (also known as systolic heart failure), a BP goal of <120/80 mmHg is recommended (Rosendorff, 2007). Although elevated SBP is more predictive of CV disease than DBP for most patients, goal achievement requires reduction of both SBP and DBP to goal values. Control of SBP is imperative and this usually results in control of DBP.


It is also known as non pharmacological treatment. JNC 7 recommends life style modification for all hypertensive and prehypertensive patients. These modifications, though difficult to implement are encouraged for everybody to prevent development of hypertension.                                                                                                                                        Life style modification can also increase response to pharmacological agent in patients that lifestyle modification alone is insufficient to reduce blood pressure (Hoffman, 2006).

Life style modification include weight control, diet that is rich in fruits and vegetables (8–10 servings/day), rich in low-fat dairy products (2–3 servings/day), but has reduced amounts of saturated fat and cholesterol, reduce daily dietary sodium intake as much as possible; ideally to not more than 65 mmol/day (equal to 1.5 g/day sodium, or 3.8 g/day sodium chloride) increase daily dietary potassium intake to 120 mmol/day (4.7 g/day). Patients who drink alcohol, should limit consumption to not more than two drinks/day in men and not more than one drink/day in women and lighter-weight persons (Alcohol consumption should not be recommended in patients that do not drink alcohol). Regular moderate-intensity aerobic physical activity; at least 30 min of continuous or intermittent 5 days/wk, but preferably daily (Grundy, 2005, Lichtenstein, 2006, Appel, 2006)


Pharmacological treatment of patients with hypertension reduces morbidity and mortality from cardiovascular disease. Effective antihypertensive therapy markedly reduces the risk of strokes, cardiac failure, and renal insufficiency due to hypertension. However, reduction in risk of myocardial infarction may be less impressive. Arterial pressure is the product of cardiac output and peripheral vascular resistance. Drugs lower blood pressure by actions on peripheral resistance, cardiac output, or both. Drugs may reduce the cardiac output by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can reduce peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels like the sympathetic nervous system (Hoffman, 2006). There are eight classes of drug, the diuretic which act by reduction of plasma volume, cardiac output and peripheral resistance, ACEI that prevents the conversion of angiotensin 1 to angiotensin II, decreasing peripheral vascular resistance, B-blockers (decrease demand of myocardial oxygen consumption, antagonize catecholamine, reduce rennin activity), Angiotensin II receptor antagonist antagonize the effects of angiotensin II through AT1 receptor, CCB relax arteriolar smooth muscle and decrease peripheral vascular resistance, central sympatholic agents decrease sympathetic outflow,  alpha 1 adrenergic antagonists antagonize the alpha constricting action on arterioles and veins and vasodilators Relax vascular smooth muscle and decrease peripheral resistance


When monotherapy fails to produce optimal control of blood pressure, combination therapy using antihypertensive drugs of different mechanisms of action is used to control BP (Ukwe and Ubaka 2012). Currently the use of monotherapy compared to combination agents in management of hypertension is being discussed. Combination therapy is treatment with two or more agents administered separately or in a fixed-dose combination pill (Frank, 2008) and required by majority of patients with hypertension to reach target blood pressure. Owing to the dismal prognosis of hypertension in Nigeria, majority of people with hypertension will require at least two antihypertensive medicines to achieve recommended goal BP.

Antihypertensive therapy is also intended to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life, so combination of antihypertensive agents from different classes may offset adverse reactions from each other, such as a diuretic decreasing edema occurring secondary to treatment with a calcium channel blocker. Other additional benefit may be to improve compliance.

Potential disadvantages include increased risk of adverse events and drug-drug interactions, and patients’ perception that taking more medications is interpreted as a more poor disease state by the patient (this may be partially addressed by the use of a fixed-dose combination pill) (Frank, 2008).

Notwithstanding the potential minus, antihypertensive combination is greatly used in Nigeria because of the potential benefits it confers to Nigerian hypertensive patients.



(SBP 140–159

OR DBP 90–99 MMHG)








(SBP >160 OR DBP

>100 MMHG)













Figure 1.1: JNC 7 algorithm for treatment of hypertension


Compelling indications
Post myocardial infarction
High Coronary disease risk
Diabetes mellitus
Chronic kidney disease
Recurrent stroke prevention
Diuretic              BB                   ACEI              ARB          ALDO ANT
Diuretic BB ACEI CCB
Diuretic ACEI
                   Figure1.2:  JNC 7 Compelling indication for individual drug classes


1.10 Pharmacoeconomics

Pharmacoeconomics is a study that identifies measures and compares the cost (i.e resources consumed) and the outcomes e.g (clinical, economic and humanistic) of pharmaceutical product and services.” It can be defined as description and analysis of costs of drug therapy to healthcare systems and society. The aim is to determine which treatment alternative produces a better outcome for the resources invested. The substance of pharmacoeconomics is “value based pricing” meaning that price of a pharmaceutical product or service should be commensurate with the outcome. Pharmacoeconomics strives to guide the utilisation of healthcare resources optimally (Malek, 1996). It includes ideas and methods from a variety of domains including statistics, clinical epidemiology, economics, decision analysis and psychometrics, etc (Wertheimer & Chaney, 2003).

1.11 Concept of pharmacoeconomics

Pharmaceutical service is an integral part of health care services. Provision of health care service consumes resources which stand as finite supply against a demand of infinite proportion (Fuchs, 1984). As resources for health care are limited, strategy for efficient distribution is pertinent. Health economics is a specialized aspect of economics developed in the 1960 (Wertheimer, 2003). It is rapidly changing and evolving. Pharmacoeconomics is a specific form of health economics that is restricted to pharmaceutical products.

Due to escalating cost of drugs in the midst of scarce resources, more classes of drug being innovated and aggressive marketing by the pharmaceutical industries, pharmacoeconomics study has become necessary to address efficient use of drug therapies. Also pharmaceutical expenditures are increasing faster than total healthcare expenditure (Wertheimer & Chaney, 2003). Economic analysis is now routinely incorporated into many clinical trials, and this type of information, in conjunction with the usual safety and efficacy data, is becoming more important to pharmaceutical companies, regulatory authorities, third party payers, and end-users (Amani & Robberstad, 2012). Pharmacoeconomic evidence can help decision-makers judge whether the therapeutic benefits produced by a new drug are worth the extra costs.

Without measurement and comparison of input and output, we have little upon which we can base the judgment about value of money spent.

In high-income countries pharmacoeconomic analysis is widely used to guide decision on priority-setting for pharmaceuticals. National Institute of Clinical Excellence (NICE) in the UK and the Canadian Agency for Drugs and Technology in Health (CADTH) are examples of institutions which have been established for pharmacoeconomic evaluation of new pharmaceutical products and technologies (Amani & Robberstad 2012). Pharmacoeconomic evaluation has also gained acceptance at hospital level in formulary decision-making in these countries. By contrast, in low-income countries applied economic evaluation studies are not only scarce, but their usefulness on essential medicine selection has also been debated (Amani & Robberstad 2012)

Pharmacoeconomics evaluation provides us with methodology to determine the treatment option which yields the maximum health gain per unit currency spent.

1.12 Methods of economic evaluation

Economic evaluation in health care is defined as the comparative analysis of alternative options in terms of their costs and consequences (Drummond, et al., 2005). Economic evaluation is the formal process of weighing benefits and costs in an incremental analysis. It is essentially a framework which draws up a balance sheet between costs and benefits to assist decision making. All methods of pharmacoeconomics evaluation involve comparison of cost and consequences of alternative courses of action.

The basic job of pharmacoeconomics is to identify, measure, value and compare cost and consequences of alternatives courses of action under consideration (Amani, et al., 2013). Two questions are to be answered in pharmacoeconomic evaluation

  • Can the two or more alternatives be compared?
  • Are the cost and consequences of the alternatives examined and compared?

Four types of economic evaluation used in pharmacoeconomics are Cost Minimisation Anaslysis (CMA), Cost Effectiveness Analysis (CEA), Cost Utility Analysis (CUA) and Cost Benefit Analysis (CBA) (Walter & Zehetmayr, 2006).


This form of analysis measures only costs, and is usually employed to the health service. It compares two or more therapeutic alternatives with equivalent outcome (effectiveness and efficacy) and need not be considered separately. This method is frequently used to compare brands with generics, different routes of administration and different settings of administration, etc (Pharmacoeconomics and outcomes, 1997). An example would be prescribing a generic preparation instead of the brand leader (lower cost but same health outcome).



Cost effectiveness is often used loosely to refer to the whole of economic evaluation. Precisely, it defines a particular type of evaluation, in which the health benefit can be defined and measured in natural units (eg years of life saved, no of patient cured, rate of remission) and the costs are measured in money. Cost-effectiveness determines cost and also assigns value to the outcome. It therefore compares therapies with qualitatively similar outcomes in a particular therapeutic area. CEA is the most commonly applied form of economic analysis in the literature, and especially in drug therapy. It does not allow comparisons to be made between two totally different classes of medicine with different form of effectiveness.

A standard method of cost-effectiveness analysis was developed by a task force of experts organized by the U.S. Public Health Service (PHS) to facilitate the comparison of different interventions (Gold, et al., 1996).

The PHS Task Force made the following recommendations:

  • Costs should be estimated from society’s perspective. The effects of an intervention on all costs should be considered, not only the direct cost of the intervention, but its effect on healthcare expenditures, and costs incurred by patients.
  • Costs and benefits should be discounted at a 3% annual rate, to reflect the lower economic value of an expense that is delayed and the higher value of a benefit that is realized sooner.
  • When the effect of the intervention on costs and benefits is not fully realized during the study period, modeling should be used to estimate the costs and benefits over the patient’s lifetime.
  • The task force also described methods of estimating the statistical significance of cost-effectiveness findings. Note that when cost-effectiveness is a primary study hypothesis, variance in costs and outcomes, and their covariance will affect the sample size.

Cost effectiveness analysis relates cost and effectiveness in a ratio known as (CER) to measure benefit of alternative treatment with similar outcomes.

……………………..equation 1.2


The treatment alternative with lower ratio is seen as a better option in a scarce society. Cost effectiveness analyses optimize cost rather than cost reduction since the alternative with the least cost might not be least expensive.

In cost effectiveness analysis, analysts first make use of principle of dominance, the more effective and less expensive is known as dominant while the less effective and more costly is known as dominated (Whittington, 2008). When a treatment is more effective and more costly, analysts must justify the additional cost of the greater effectiveness by calculating incremental cost effectiveness ratio. Cost effectiveness analysis may also be expressed in terms of Incremental Cost Effectiveness Ratio (ICER) represented by the following equation:


……………………equation 1.3


Incremental cost effectiveness ratio reveals the cost per unit benefit of switching from one treatment to another. The ratio is most useful when the outcomes are expressed in quality adjusted life years (QALY). The cost-effectiveness ratio represents a measure of how efficiently the proposed intervention can produce an additional QALY.


It has similarity to cost effectiveness in that the costs are measured in monetary terms. The outcome is measured in utility values. The most widely used unit of utility is QALY. QALY gives us the opportunity to measure the elongation of life and the quality of life lived in those years in a single unit. Since outcome of treatment is not directly dependent on the disease state, CUA can measure the cost per QALY achieved with different classes of drugs eg decision makers can set priority between treatment of hypertension and treatment of asthma. From utility we can estimate patients’ preference for a particular intervention in terms of patient state of wellbeing.

Cost utility ratios can be used to select the form of treatment with highest unit of utility in a particular disease type.


It is the oldest form of economic analysis. Any treatment option with more benefit than cost is considered worthwhile. In this analysis, the cost and benefit are measured in monetary units. Concept of contingent valuation provides techniques for assessing cost-benefit for individual patients. The techniques used in the concept are willingness to pay and willingness to accept approach.

The disadvantage is that some important treatment outcome are difficult to quantify in monetary terms eg the cost of returning to work, cost of losing one’s sight. CBA may also seem to discriminate against those in whom a return to productive employment is unlikely, eg the elderly, or the unemployed. These limitations make it a rare choice in pharmacoeconomics analysis in present days.

However the virtue of this analysis is that it may allow comparisons to be made between very different areas, and not just medical, e.g. cost benefits of expanding university education (benefits of improved education and hence productivity) compared to establishing a back pain service (enhancing productivity by returning patients to work).

1.13 Types of pharmacoeconomic studies

There are three ways of conducting pharmacoeconomic evaluations:

  • Prospective
  • Retrospective
  • Modeling

Prospective studies are experimental studies that can be part of a randomized clinical trial or strictly an economic evaluation. This type of study involves comparison of treatment between users and non users that are followed from some point in the past to the present. They usually involve much expenses and time and are the least useful method of economic evaluation.

Retrospective studies are seen as the best study method in economic evaluations. Data concerning cost and benefit are obtained from data base and analyzed.

Modeling is an inexpensive and effective way of illustrating existing available data regarding the costs and outcomes of alternative therapeutic interventions. Modeling frameworks include decision trees, influence diagrams, Markov analysis, discrete event simulation and systems dynamics. In healthcare, it is an established framework to inform decision making under conditions of uncertainties (Weinstein & Fineberg, 1980; Sox, et al., 1988; Hunink, et al., 2001).

1.14 Cost analysis

Cost in health economics has a broad definition. It depends partly on the perspective or point of view taken in analyzing cost. In health economics, costs are defined in the economic meaning of the term and understood as the financially quantified consumption of resources. Cost is usually assessed in monetary terms.


Direct costs comprise all consumption of resources resulting from a treatment or therapy and directly attributable to this. Direct costs include direct medical and direct non-medical costs. Direct medical costs arise directly from the treatment (e.g. diagnosis, drug therapy, medical care, in-patient treatment, etc). Direct nonmedical costs arise from the consequences of the disease or treatment (e.g. transport costs, care services, etc.). They are easier to calculate when they are paid for rather than offered by a family member.


Indirect costs comprise of consumption of resources not directly in relation to the treatment of the disease. This includes losses of productivity resulting from illness and premature death.

Intangible cost they include the cost pain, worry, anxiety and loss of enjoyment by the patient or their family. It cannot be calculated in monetary terms but sometimes calcualted in terms of QOL.

1.15 Consequences

Consequences are also known as outcomes. It simply means effects from the treatment.  Usually a favorable outcome is expected from the course of treatment taken but sometimes a negative outcome may occur. Assessment of outcome can be in monetary, non monetary and natural units. Outcomes of a treatment may be categorized into.


Economic outcome: it measures direct, indirect and intangible costs of the treatment.

Clinical outcome: measures medical events that occur during treatment. They include physiological or biochemical, morbidity- or mortality-related parameters. Final endpoints and intermediate endpoint also measure clinical outcome.

Humanistic outcome: it is a type of treatment outcome that measures quality of life of the patient, the satisfaction of the patient.

Outcomes can be assessed objectively or subjectively. Objective assessment may be done simultaneously by the clinician, economists and the care giver while subjective assessment: it is usually reported by the patient and measures humanistic outcome (Whittington, 2008).

1.16 Why do we study pharmacoeconomics

  • Accepted evaluation for reimbursement.
  • Informs clinical decision and policy making.
  • Presents the value of drug in form of cost and benefit to the public and healthcare professional.
  • Informs choice between two treatment options.
  • Employed by pharmaceutical companies in presenting value of their drugs to physician, policy makers.

1.17 Review of previous study

A number of economic analyses have been done in relation to hypertension and some are summarized below:

(Ekwunife, et al., 2013) conducted a study to analyze the cost utility of antihypertensive medication in Nigeria. The authors employed a Markov process model to calculate the clinical outcome and cost of thiazide diuretics; BB; CCB and ACEI during a life cycle of 30years for 1000 patients stratified into three cardiovascular risk groups. They also employed Monte Carlo simulation to calculate probabilistic cost effectiveness analysis.

The authors concluded that thiazide diuretic followed by ca channel blockers could be a feasible strategy in ensuring better control of hypertension in Nigeria.


Adigun et.al in 2003 carried out a cross sectional study to evaluate the pharmacoeconomics of old and newer antihypertensive in South west Nigeria. The Pharmaco-economic comparison of the different drug classes showed that for every US dollar ($) spent per month, the percentage of treated patients attaining normotension was 18.6% for Diuretics, 4.73% for CCB, 3.5% for ACEI+D and 13.6% for methyldopa+thiazides. A combination of ACEI+CCB or D was the preferred treatment for hypertensive-diabetic Nigerians, but only 24% attained a BP of < 130/85mmHg. The study concluded that there is a shift in trend to a more rational and efficacious treatment of hypertension over a 10 year period (Adigun, et al., 2003).


In 1995 Johannesston, analyzed cost effectiveness of antihypertensive drug treatment in different group of patients in Sweden. The results of the study showed that antihypertensive treatment is generally cost effective in middle aged and older patients with a DBP of > or = 90mmHg in Sweden. The study questioned the cost effectiveness of treating younger patients with mild hypertension (Johannesston, 1995).


In 2002 a cost effectiveness analysis of different classes of antihypertensive was assessed in a population based study in Brazil. The result of the study showed that the most favorable option is the use of diuretics and beta blockers. The group concluded the study by recommending diuretics or beta blockers as more cost effective compared to ACE inhibitors and calcium channel blockers (Dias da Costa, et al., 2002).


A study was done to analyze the cost-effectiveness of lifetime antihypertensive therapy with angiotensin II receptor blocker (ARB) monotherapy, calcium channel blocker (CCB) monotherapy, or ARB plus CCB (ARB+CCB) combination therapy in Japan. Using the results of large-scale clinical trials and epidemiological data, the group constructed a Markov model for patients with essential hypertension. The three treatment strategies were compared in hypothetical 55-year-old patients with systolic blood pressure (SBP) of 160 mmHg in the absence and presence of comorbid diabetes. Olmesartan medoxomil 20 mg/d was the ARB and azelnidipine 16 mg/d the CCB in our model. On-treatment SBP was assumed to be 125, 140, and 140 mmHg in the ARB+CCB, ARB alone, and CCB alone groups, respectively. Costs and quality-adjusted life years (QALYs) were discounted by 3%/year. The ARB+CCB group was the most cost-effective both in male and female patients with or without diabetes. In conclusion, ARB plus CCB combination therapy may be a more cost-effective lifetime antihypertensive strategy than monotherapy with either agent alone (Saito, et al., 2008).


A cost of illness study was conducted in Malaysia to quantify the total direct and indirect costs of hypertension management. It was a retrospective study that estimated the direct medical costs for 300 hypertensive patients. The cost considered included health care practitioners’ services, medicines and laboratory tests and through follow up process. Indirect costs were estimated as productivity lost by hypertensive patients. The author used prevalence and incidence-based approaches to estimate the cost of illness of hypertension disease.

The results showed total direct costs to be RM1612.38, RM1741.85 and RM2718.21 for the prehypertensive, stage 1 and stage 2 hypertensive groups respectively. The total indirect costs were RM8078.70, RM6654.52 and RM7511.41 and concluded that the direct costs attributable to hypertension disease were higher in higher blood pressure groups and direct costs of hypertension are mainly dependant on the costs of antihypertensive agents. The group recommended that efforts should focus on improving the awareness of the both clinical and economic benefits of preventing hypertension in the society (Alefan, et al., 2009)


Another study was done to know the incremental expenditure involved with treating hypertension in 2001 in United States. They conducted a Medical Expenditure Panel Survey on the identified hypertensive patients from among the civilian non-institutionalized US population. After adjusting demographics and co-morbidities, authors found out that the total incremental direct annual expenditure for hypertensive patients in the year 2001 were estimated to be more than US$54.0 billion. The mean incremental direct annual expenditure for individual hypertensive patient was US$1.131 (Balu and Thomas, 2006).


Richardson and his group did a study in 2004 with the aim of assessing the potential cost effectiveness of implementing new guidelines for the treatment of hypertension in general practice in United Kingdom. The study revealed that implementing new guidelines for the detection, management, and treatment of hypertension in primary care setting is more costly than the implementation of previous guidelines, but more effective in reducing the risk of cardiovascular disease (Richardson, et al., 2004).


In South Africa, a group analyzed the cost effectiveness of hypertension guideline based on blood pressure level in comparison with one based on absolute cardiovascular disease (CVD) risk for developing countries. The results of the study showed that in South Africa, current guidelines based on blood pressure levels are both more expensive and less effective than guidelines based on absolute risk of cardiovascular disease. The study noted that the use of quantitative risk based guidelines for treatment of hypertension could free up major resources for other pressing needs, especially in developing countries (Gaziano, et al., 2005).


In 2012 a study assessed the financial implication and cost effectiveness of hypertension treatment in a rural town in south west of Nigerian by reviewing 250 rural patients with primary hypertension at a regional hospital. They reported that the median number of prescribed drugs was two (range1-4). Mean cost of treatment was ₦1440±560 ($9.6±3.7) with 52.8% spending ≥ 10% of their income on treatment. The most cost effective therapies were methyl Dopa and diuretics with Cost-effectiveness ratios of 8 and 12.8 respectively. Patients with co-morbidities, stage 2 hypertension and those on three or four drug regimen had significantly higher treatment costs. They concluded that the financial burden of long term antihypertensive therapy appears substantial, cost reduction strategies are needed to optimize hypertension treatment in societies with limited resources (Ilesanmi, et al., 2012).


In 2012, Geroy reviewed the economic studies for first line anti-hypertensive medical treatment without co-morbidities and discussed the practical, informational and policy implications on the use of economic evaluation in Philippines. The results showed diuretics as the most cost-effective drug class for first-line treatment of hypertension without co-morbidities. The author noted an information gap on clinical data (transition probabilities, relative risks and risk reduction) and utility values on hypertension and related diseases from middle- and low- income countries. He further recommended a study on the costs of hypertension in the Philippines including in-patient, out-patient, out-of-pocket, local government and national government expenditure (Geroy, 2012).


In 2009, a study evaluated the level of awareness and control of hypertension; socioeconomic and educational level; and also assessed the cost-effectiveness of the main pharmacologic classes of antihypertensives, as monotherapy and combination therapy in Brazil. It was a randomized and cross-sectional populational study in over 40-year-old patients. Results showed that 72.9% of the hypertensive patients knew about their disease. The rates of awareness were similar in different social classes and educational levels, however, blood pressure control varied. B-Blockers were the most effective drugs to control blood pressure with no differences being observed between monotherapy and combinations. Diuretics were the most cost-effective. The levels of awareness and control were high compared with developed countries, most evident in the higher social classes and higher education levels (Moreira, et al., 2009)


(Tisuji, et al., 2012) conducted a randomized clinical trial in Brazil in 2011 and studied the cost-effectiveness ratios of the traditional treatment (hydrochlorothiazide and atenolol) and the current treatment (losartan and amlodipine) in patients with grade 1 or 2 hypertension (HT1-2). For patients with grade 3 hypertension (HT3), a third drug was added to the treatment combinations: enalapril was added to the traditional treatment, and hydrochlorothiazide was added to the current treatment. The study concluded that the traditional treatment is more cost-effective (US$/mm Hg) than the current treatment in the HT1-2 group. There was no difference in cost-effectiveness between the traditional treatment and the current treatment for the HT3 group.


In 2004 a study to determine the point in time that initiation of irbesartan treatment in hypertensive patients with type 2 diabetes and renal disease will be most cost-effective was published. Palmer et al created two stages for introducing irbesartan: early irbesartan 300 mg daily (initiated with microalbuminuria) and late irbesartan (initiated with overt nephropathy). Result of the study showed that early and late irbesartan treatment in 1,000 patients were projected to save (mean ± SD) $11.9 ± 3.3 million and $3.3 ± 2.7 million, respectively. Early use of irbesartan added 1,550 ± 270 undiscounted life-years (discounted 960 ± 180), whereas late irbesartan added 71 ± 40 life-years (discounted 48 ± 27) in 1,000 patients. Early irbesartan treatment was superior under a wide-range of plausible assumptions. The conclusion is that early irbesartan treatment was projected to improve life expectancy and reduce costs in hypertensive patients with type 2 diabetes and microalbuminuria. Later use of irbesartan in overt nephropathy is also superior to standard care, but irbesartan should be started earlier and continued long term (Palmer, et al., 2004)

 1.18 Objectives of the study

The main objective of this study was to evaluate the cost effectiveness of antihypertensive combination therapies recommended by JNC 7 in University of Nigeria Teaching Hospital Ituku Ozalla.


Specific objectives:

  • To assess the pattern of use of JNC 7 specification in the management of hypertension in University of Nigeria Teaching Hospital Ituku Ozalla.
  • To examine the outcome of the treatment combinations on surrogate end point (BP)
  • To assess the cost of blood pressure control using the treatment combinations (2 drug combinations and more than 2 drug combinations) for stage1, stage 2 and sample population as a whole.
  • To evaluate the cost effectiveness ratio of using 2 drug combinations and more than 2 drug combinations therapy for stage 1, stage 2 and sample population as a whole.

To assess the incremental cost and incremental effectiveness associated with the treatment combinations.


Do you need help? Talk to us right now: (+234) 08060082010, 08107932631 (Call/WhatsApp). Email: edustoreng@gmail.com.

Disclaimer: This PDF Material Content is Developed by the copyright owner to Serve as a RESEARCH GUIDE for Students to Conduct Academic Research.

You are allowed to use the original PDF Research Material Guide you will receive in the following ways:

1. As a source for additional understanding of the project topic.

2. As a source for ideas for you own academic research work (if properly referenced).

3. For PROPER paraphrasing ( see your school definition of plagiarism and acceptable paraphrase).

4. Direct citing ( if referenced properly).

Thank you so much for your respect for the authors copyright.