Angiotensin Receptor Blockers - Assignment Example

? Angiotensin Receptor Antagonists (ARBs) and Calcium Channel Blockers (CCB) – Analysis of a Clinical Trial of Introduction Often referred to as angiotensin receptor blockers (ARBs), angiotensin II receptor antagonists (AT1-receptor antagonists) are pharmaceutical products used to moderate the renin-angiotensin-aldosterone system in the body. The main uses to which ARBs are put include the treatment of diabetic nephropathy, congestive heart failure and hypertension.1 However, the primary usage of ARBs is in the treatment of hypertension in which a patient’s system is not able to tolerate angiotensin converting enzyme (ACE) inhibitor remedy. Since ARBs do not hinder the breaking down of bradykin, they are seldom linked with the dry and persistent cough and angioedema, which work against ACE inhibitor treatment.2 Besides hypertension, ARBs are currently extensively used in managing heart failure in ACE inhibitor-intolerant patients. Research findings also support the effectiveness of ARBs in benefiting type II diabetic hypertensive patients. Thus, ARBs are used to slow down the progress of diabetic nephropathy. The potencies of ARBs have been shown to vary with the level of dosage and blood pressure control. In addition, in a clinical setting, the ARB agent used depends on the extent of the expected response.3 In addition to treating hypertension, a few of these pharmaceutical products have uricosuric effects whereas some ARBs, such as losartan (Cozaar), were found to improve sexuality in 88% of hypertensive males with sexual dysfunction in a 12-week study in which subjects were treated with the ARB.3 Through AT1-receptor stimulation, angiotensin II acts as a major stress hormone.4 Given that ARBs block these receptors, they are considered for the treatment of stress-related disorders in addition to their elicitation of anti-hypertensive effects. ARBs have also been associated with a negative correlation with Alzheimer’s disease. For example, in 2008, the United States Department of Veteran Affairs analysed records of about five million patients to establish the various types of anti-hypertensive drugs used and their Alzheimer’s disease-related outcomes. It was reported that patients who used ARBs were 40% less likely to develop Alzheimer’s disease compared to those placed under other antihypertensive medications.4 Although ARBs are always well tolerated by many, they are associated with several adverse side effects such as headache, hyperkalemia and dizziness. Other less frequent adverse side effects of ARBs use are dyspepsia, rash, diarrhea, muscle cramps, back pain, renal impairment, nasal congestion, impaired liver function, lowered hemoglobin levels and pharyngitis.5 Moreover, despite ARBs being used to help avoid cough and angioedema, these conditions may still be encountered in certain situations.6 What is more, there is a chance of irritable reactivity for patients with angioedema to ACE inhibitor therapy. This paper explores angiotensin II receptor blockers (ARB) and calcium channel blockers (CCB) with respect to the pharmacology of angiotensin receptors and their therapeutic use in treating hypertension. Second, the paper summarises the design and results from clinical trials conducted to determine and ascertain the efficacy of Valsartan and Amlodipine in the treatment of hypertension.6 Further, the paper explores the theories and applications of clinical trial design with respect to the inclusion and exclusion criteria used, patient randomisation and bias minimisation.6 The other aspects of clinical trial design to be covered are Kaplan-Meier plots and hazards ratios. Mechanisms of Action Angiotensin and CCBs Formed from angiotensin I in an angiotensin-converting enzyme (ACE, kininase II)-catalysed reaction, angiotensin functions in its capacity to cause blood vessel muscles to contract, thus narrowing blood vessels and increasing the pressure of blood in these vessels, hence hypertension. Angiotensin II receptor blockers (ARBs) prevent the action of angiotensin II by blocking angiotensin II from binding to angiotensin II receptors on blood vessels.7 Consequently, blood vessels are dilated and blood pressure is reduced. This reduction in blood pressure enables the heart to pump blood with a lot of ease and slows down the progression of diseases such as diabetes and kidney failure.7 These ARBs effects are similar to those of angiotensin converting enzyme (ACE) inhibitors. However, ACE inhibitors’ mechanism involves the prevention of the formation of angiotensin II. Thus, ACE does not block the binding of angiotensin II on blood vessel muscles.7 The other effects of angiotensin II, which is the primary pressor agent of the renin-angiotensin system, are cardiac stimulation, stimulation of synthesis and release of aldosterone, and renal reabsorption of sodium. Since angiotensin II receptor blocker (ARB), such as Telmisartan, blocks the vasoconstrictor and aldosterone secreting effects of angiotensin II through the selective blocking of the binding of angiotensin II to the AT1 receptor in body tissues, its action is independent of angiotensin II synthesis pathways. Among the tissues from which the binding of angiotensin II is blocked are the vascular smooth muscle and the adrenal gland. Thus, ARBs block a step in the renin-angiotensin-aldosterone system (RAAS) as shown in the diagramme below (retrieved from http://www.zuniv.net/physiology/book/chapter24.html). As mentioned earlier, calcium channel blockers (CCBs) function by disrupting the flow of calcium ions (Ca2+) through calcium channels. They are mainly used as antihypertensive medications due to their ability to reduce blood pressure. In particular, CCBs are used to correct the stiffness of large vessels, which causes high systolic blood pressure. The functioning of the CCBs is based on the concentration of calcium ions (Ca2+), which is always higher on the outside of cells than in the inside. Calcium channels are embedded in the membrane of some cells from where they receive signals of changes in CA2+ concentration in and outside of the cell. The channels then open and calcium is taken into the cell. Calcium channel blockers’ role is to reduce or prevent the opening of these channels, thus reducing these effects of the changes in calcium concentration on different cells. Diagram 1 Mechanism of action of angiotensin II Diagram 2 Mechanism of action of CCB The mechanism by which ARBs act has been an area of focus for many researchers. Since ARBs are antagonists to AT1-receptor antagonists, they inhibit the activation of angiotensin II AT1 receptors. The effects of this inhibition of AT1 receptors include vasodilatation, the reduction of vasopressin as well as lowered secretion of the hormone aldosterone.8 In combination, all these effects of AT1-receptor blockage result in reduced blood pressure. Although their mechanism of action could be the same, the efficiency of ARBs depends on several factors including pharmacokinetic and pharmacodynamic ones such as pressor inhibition, AT1 affinity and biological half-life. Pressor inhibition is the extent to which angiotensin II’s blood pressure-increasing effect (pressor) is inhibited. Nonetheless, the extent to which pressor is inhibited does not directly measure the efficacy with which blood pressure has been lowered.9 On the other hand, AT1 affinity refers to the specificity with which the drug is attracted to the corresponding receptor. According to the US FDA PI rates, the AT1 affinities for some of the medicines are shown in the table below.10 Medicine At1 Affinity Losartan 1000-fold Irbesartan 8500-fold Valsartan 20000-fold Telmisartan 3000-fold Azilsartan Greater than 10000-fold Biological half-life is the other factor that affects the efficacy of ARBs. For some of ARBs, the US FDA PI outlines the following half-lives.10 ARB Half-Life Losartan 6–9 hours Telmisartan 24 hours Irbesartan 11–15 hours Azilsartan 11 hours Valsartan 6 hours Angiotensin Receptor Antagonists (ARBs) and Calcium Channel Blockers (CCB) Calcium channel blockers are the other drugs widely used in the treatment of hypertension.10As evidenced in many clinical trials, ARBs and CCBs have been shown to have tremendous organ-protection abilities, not to mention their other antagonistic effects. Yet, not many studies have been conducted to explore the impacts of CCBs and ARBs as monotherapies on clinical lab constraints in patients of associated hypertension and other diseases such as type 2 DM. Design and Theory of Clinical Trials In these clinical trials, most of which are conducted in institutions of higher education or pharmaceutical firms’ laboratories, data is often used to classify groups of latest ARB consumers and match the propensity scores with new users with associated less severe and moderate hypertension and type 2 DM. In such clinical trials, approaches such as the multivariate-attuned deterioration are used to modify for the differences among CCB and ARB users. The other use to which the multivariate-adjusted regression model is put in these trials is the comparison of lab parameters such as total cholesterol (TC), Triglyceride levels in the serum, non-fasting glucose levels, potassium and sodium levels, platelet (PLT), hemoglobin A1c (HbA1c), white blood cell (WBC), red blood cell (RBC) and counts among other parameters.11 Among the conspicuous findings of ARB and CCB clinical trials are a reduction in the RBC, serum TC, HbA1c, hemoglobin and hematocrit count in ARB users. On the other hand, CCB users often report a reduction in total serum cholesterol and hemoglobin from the baseline to the exposure.12 Notably, the decrease in RBC tally, hematocrit and Hb1Ac always exceeds that of CCB users. Similarly, the rise in serum potassium was considerably greater in users of ARB than it is in those placed under CCB. Different methodologies and materials have been used in clinical trials exploring the benefits of ARBs and CCB besides their antihypertensive effects. The first factor considered in these trials is the source of the data to be used. In many cases, clinical databases from a centralised data repository are used. The advantage of such databases is that they contain integrated data from separate databases.12 Examples of data used in this regard are data from laboratory results and medication order entries. Thus, databases of affiliated health facilities have proved rather useful in this regard. Importantly, many trials collect prescription data of hundreds or thousands of patients, which are then linked to give the diagnosis, demographic and lab result data. The second aspect of clinical trial design worth exploring is the study population. In many such trials, 20-year old and older patients with moderate hypertension are often targeted.12 Specifically, such patients may have just been treated with ARB or CCB monotherapy for a given period settled on by the concerned researchers. The standard measurement period for most clinical trials on the efficacy of ARBs and CCBs varies. Noteworthy, many studies settle on 12 months of non-exposure to CCB or ARBs. The outcome measurement or the exposure period also varies and may range from two months to years. Many trials have achieved a mean exposure period of about 240 days for ARB and CCB users alike.12 Among the data often collected in clinical trials on ARBs and CBBs efficacy against hypertension and other diseases such as diabetes mellitus are levels of triglyceride (TG), sodium, potassium, alanine aminotransferase (ALT), total serum cholesterol (TC), creatinine, aspartate aminotransferase (AST), non-fasting blood glucose and hemoglobin A1c (HbA1c).13 Other major measurements are white blood cell (WBC), red blood cell (RBC) and platelet (PLT) counts. Generally, these data are collected at a date near to the commencement of ARB or CCB therapy in the model period and at a date nearest to the end of the exposure period or the period during which ARB or CCB therapy has been implemented. The core elements of data collected from patients include their demographics data, which encompass sex and age, their usage of medication, medical history and lab results. Among the diseases often targeted and found in hypertensive patients included in these trials are ischemic heart condition, cerebrovascular disease, kidney disease, thyroid gland disease, liver disease, rheumatoid arthritis, hyperlipidemia and gout.14 Researchers also record any drugs that patients use prior to the commencement of CCB or ARB monotherapy. Interestingly, chemotherapeutic drugs, steroids, gout drugs, potassium preparations, diuretics, immunosuppressive drugs, antipsychotics and hypoglycemic drugs such as oral hypoglycemic medicaments have been found to be largely used by hypertensive and diabetic patients. Also used by such patients are lipid-reducing drugs such as histamine H2 receptor blockers, statins, fibrates and thyroid drugs.15 To reduce bias in studies comparing the efficacy of CCB and ARB monotherapy, researchers often match the CCB and ARB user groups by a propensity score using a corresponding five-number greedy 1:1 algorithm. In fact, this is the preferred and standard method by which bias is reduced, given its ability to balance setting covariates. Hence, many a report has used this model. Among the covariates used to produce the propensity score in the clinical trials are medical history, age, previous drug use and gender.16 Prior to and after the matching of the propensity score, researchers always compare the frequency of all the standard covariates. This comparison is done using the t-test for uninterrupted variables and chi-squared test for explicit data. After matching the propensity scores and adjusting the covariates, the mean values of the laboratory parameters are compared at the start, during and after the period of exposure to ARBs and CCBs.16 These studies often have certain consistent findings. For instance, for users of ARB, significant reduction is recorded in serum TC, HbA1c, hemoglobin, hematocrit and RBC count whereas for CCB users, there is a reduction in the levels of serum TC and hemoglobin. CCB and ARB comparison studies have consistently shown that adverse hematological effects and electrolyte imbalance are greater in patients placed under ARB monotherapy compared to those placed under CCB monotherapy.17 These findings support the common knowledge that while they have protective effects on several body organs, renin-angiotensin system inhibitors, ACEIs and ARBs sometimes result in anemia. Hence, valsartan has been shown to decrease hematocrit in recipients of kidney transplantation while losartan decreases hematocrit, hemoglobin and erythrocyte count in kidney transplant recipients.18 Sample Study Comparing Valsartan and Amlodipine Efficacy In a study conducted by a team of researchers at Ospedale L. Sacco University in Milan, Italy, in 2003, the efficacy of valsartan and amlodipine in the treatment of systolic hypertension in elderly patients was compared. This was a randomised, double-blind, active-controlled, parallel-group study, which aimed at comparing valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients. The study was based on the postulation that in some antihypertensive therapies, efficacy and recovery are hampered by certain adverse effects, which depend on the dosage prescribed and taken.19 In addition, that angiotensin II receptor blocker valsartan has been proved to lower blood pressure in a dose-related manner, accompanied with minimal dose-limiting adverse side effects.19 Similarly, amlodipine besylate is a powerful dihydropyridine calcium channel blocker with dose-associated antihypertensive ability.19 However, the latter drug has possible dose-limiting adverse effects, especially peripheral edema. In particular, this study sought to identify and compare the risks/benefit ratios and profiles of valsartan and amlodipine in elderly people suffering from isolated systolic hypertension (ISH).19 The study findings indicated that the most consistent and statistically significant difference between the medications was blood pressure control. It was established that amlodipine-based therapy was significantly more efficacious in reducing blood pressure compared to valsartan, especially during the early phases of treatment. The study was based on the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE), which is always used to compare the performance and effects of antihypertensive treatment agents. Covering 35 outpatient centres in Italy, the randomised, active-controlled and double-blind study ran for 24 weeks. The target group, aged between 60 and 80 years, received ISH oral medication of valsartan 80-mg capsules or amlodipine 5-mg capsules once a day.19 At the 8 week mark, the dosage of elderly patients with poorly controlled systolic blood pressure was titrated to 160 mg of valsartan or 10 mg of amlodipine once per day.19 At the 16 week mark, for patients whose systolic blood pressure remained poorly controlled, a low dosage of diuretic (hydrochlorothiazide [HCTZ] 12.5 mg) was added to the treatment programme for 8 extra weeks. The researchers then assessed patient tolerability during all study visits via interviews and physical examination. Of the 421 randomised participants, 231 were women while 190 men with a mean age of 69 years. 208 of these patients were placed in the valsartan therapy while 213 in the amlodipine one.19 The efficacy of valsartan-based treatment and that of amlodipine-based treatment in reducing systolic blood pressure was found to be similar.19 After doubling the dosage at the 8 week mark, efficacy in reducing the systolic blood pressure was observed to increase significantly from the baseline for both therapies.19 Notably, the frequency at which adverse side effects occurred with the 10mg amlodipine dosage was higher than in the case of doubling valsartan dosage to 160 mg. In fact, the increase in the latter case was clinically irrelevant. Generally, it was noted that 31.9% of the patients under amlodipine and 20.2% of those under valsartan therapy had adverse side effects.19 These groups reported peripheral edema rates of 26.8% and 4.8%, respectively. From this study and its results, it may be said that in elderly patients with ISH, valsartan therapy or its combination with HCTZ 12.5 mg has same efficacy but enhanced tolerability compared to amlodipine-based medication.20 The findings of this comparison study on the efficacy of valsartan therapy and amlodipine-based treatment, as in the case of other trials, are always displayed in Kaplan-Meier plots, an example of which is shown below. This curve shows the success or efficacy of a drug in promoting patient survival. The chances of survival are thus higher in patients with reduced chances of developing adverse effects, as shown in graph 2. References 1. Rowland DY, Simon DI, Fang, JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncology. 2010;11(7):627. 2. Weinberg MS, Adam J, Weinberg R, Cord B, Martin H. Regression of dilated aortic roots using supra-maximal and usual doses of angiotensin receptor blockers. American Journal of Hypertension. 2003;16(5):A259. 3. Ersoy A. Anemia due to losartan in hypertensive renal transplant recipients without post-transplant erythrocytosis. Transplant Proc. 2007;37:2150. 4. Reudelhuber TL. The continuing saga of the at2 receptor: a case of the good, the bad, and the innocuous. Hypertension. 2005;46(6):1261. 5. Lopez V, Martin M, Cabello M., Sola E. Renin-angiotensin system dual blockade using angiotensin receptor decreases severe proteinuria in kidney transplant recipients. Transplant Proc. 2010;42:2885. 6. McMillan J. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers. Therapy, Clinic and Risk Management. 2009;1(5):552. 7. Kitamura N, Takahashi Y. Angiotensin II receptor blockers decreased blood glucose levels. Cardiovascular Diabetology. 2007;1(6):26. 8. Granger C. CHARM investigators and committees: effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-overall programme. Lancet. 2003; 362:759. 9. Cassis P, Conti S, Remuzzi G, Benigni A. Angiotensin receptors as determinants of life span. Pflugers Archives. 2010;459(2):325. 10. Coffman T, Conti S. Angiotensin FDA drug safety communication: no increase in risk of cancer with certain blood pressure drugs – angiotensin receptor blockers (ARBs). U.S. Food and Drug Administration; 2011. 11. Laurent S. Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European society of hypertension (ESH) and of the European society of cardiology (ESC). Journal of Hypertension. 2007;25:1187. 12. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:207. 13. Chrysant SG. Proactive compared with passive adverse event recognition: calcium channel blocker-associated edema. Journal of Clinical Hypertension (Greenwich). 2008;10:722. 14. Caulfield M, Collins R, O'Brien E. ASCOT investigators: prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required: a multicentre randomised controlled trial. Lancet. 2005;366:906. 15. Kunz R, Friedrich C, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:48. 16. Gentile G, Angeli F, Verdecchia P. Optimal therapy in hypertensive subjects with diabetes mellitus. Current Atherosclerosis Report. 2011;13:176. 17. Li NC, Lee A, Lawler E. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340(9):b5465. 18. Fujita T, Ando K. Cilnidipine versus amlodipine randomised trial for evaluation in renal disease (CARTER) study investigators: antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease. Kidney Int. 2007;72:1543. 19. Malacco E. Val-system study. Clinical Therapy. 2003;1(11):2765–80. 20. Plat F, Smith B. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine. Lancet. 2004;363(9426):2022. Read More