Efficacy of ACEI and ARBs in the Treatment of Myocardial Infarction - Example

EFFICACY OF ACEI AND ARBS IN THE TREATMENT OF MYOCARDIAL INFARCTION Examination of the basic concepts of design, methodology and analysis of clinical trial data Name Course Tutor 30 September 2012 Introduction Cardiovascular diseases such as myocardial infarction and stroke are major contributors to death and disability cases in the world [1]. Antihypertensive medications are today used to treat various cardiovascular diseases [2]. Antihypertensive drugs function by acting on the rennin-angiotensin system, and the efficacy of these drugs has been found to improve when they are co-administered with other drugs like diuretics, adrenergic receptor antagonists and calcium channel blockers [2,13]. Different factors have contributed to the way these medicines are administered and used among different individuals, a situation that has ensured that proper clinical guidelines are followed in the process of selecting the appropriate medicines for individual patients [3]. As a result, it becomes necessary to review the existing clinical trials concerning efficacy of antihypertensive medicine. Pharmacology of ACE Inhibitors (ACEI) and Angiotensin receptor antagonists (ARBs) Cardiovascular diseases exhibit one unique characteristic: blood pressure is normally common as the primary issue of concern [4]. Renin performs an important role in the renin-angiotensin system, where, rennin stimulates the creation of a protein element known as angiotensin I. This protein element is later converted to angiotensin II. The conversion succeeds as a result of presence of angiotensin-converting enzyme that can be found in the lungs. At the moment, angiotensin II has been found to be the most dominant constrictor of blood vessels [5,13]. When blood vessels are constricted in the body, as aided by angiotensin II, the blood pressure is usually elevated, a situation that contributes to emergence or sustenance of a cardiovascular disease. The angiotensin II contributes in special way in this process; it has been established that angiotensin II stimulates the secretion of aldosterone [6]. Aldosterone is a hormone produced in the adrenal glands and it increases blood pressure. In general, what is described here is a pattern in form of a chain of blood pressure that actively participates in regulating hormones and the chain is known as rennin-angiotensin-aldosterone (RAA) hormonal system. For a long time now, the RAA system has been established to play an important role in regulating blood pressure in the body of humans. But, a number of factors have been found to distract the smooth functioning of the RAA system. Some of these factors include hereditary and genetic factors, nutritional factors, body weight factors, activities that humans engage in and specific medicines that may affect the RAA system [7,13, 16]. In order to respond to these factors to ensure the RAA system functions properly, a number of lifestyle modifications and medical treatment have been used in notable cases where the blood pressure is > 130/80 mm Hg [4]. Although a number of blood pressure, anti-hypertensive, medications have been identified, there are two classes of anti-hypertensive medications that have been identified to provide positive effects on the RAA system. The two classes of drugs are angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) [4]. Consensus among the medical professionals concerning guidelines to be used in treating and managing hypertension indicate that the use of ACE inhibitors and ARBs constitute the effective initial therapy due to their proven benefit in lowering cardiovascular mortality and progression of both retinopathy and nephropathy [5-6]. At the same time, there has to be administration of second and third-line treatment with diuretics, -Blockers pr calcium channel blockers, which should be tailored to the individual patient. In most cases Blockers are prescribed in patients who have had a myocardial infarction, heart failure or for rate control in atrial fibrillation [6]. The use of ARB drugs and ACE inhibitors are used to lower blood pressure, where they function by jamming definite and particular steps in the RAA chain [6]. ACE inhibitors can be said to function as follows. They dilate the arterioles and veins by preventing the creation of angiotensin II and also by stopping the bradykinin metabolism. The vasodilation effect realised minimises pressure in the arterioles, thereby making the heart function properly. At the same time, it facilitates the renal excretion of sodium and water by suffocating the impacts of angiotensin II in the kidney. Furthermore, ACE inhibitors suffocate angiotensin II stimulation of aldosterone secretion, a situation that results into reduction of blood volume, venous pressure and also the pressure in the arterioles. Lastly, ACE inhibitors block cardiac and vascular remodeling that is connected to hypertension, heart failure and myocardial infarction [7]. ACE inhibitors are adopted in diverse therapeutic uses such as treatment of hypertension, heart failure and myocardial infarction. ACE inhibitors have been found to be effective in long-term when compared to other agents, especially in treatment of these cardiovascular diseases [8]. For instance, they have been found to reduce morbidity and mortality among patients with heart failures. At the same time, they have demonstrated to be effective in improving survival, reducing frequency of hospitalization, preventing disease progression and improving quality of life both symptomatic and asymptomatic patients who have ventricular systolic dysfunction and heart failure [4]. On the other hand, angiotensin receptor blockers (ARBs) function in such way that they hamper the angiotensin II (AT1type) receptor [8]. The blockage for angiotensin II normally takes place on the small arteries, also known as arterioles. When this happens, the angiotensin is rendered impotent in enabling the arteries to constrict, thereby lowering the blood pressure [5]. Focus on angiotensin II is informed by the fact that this element is the most powerful constrictor of blood vessels. Therefore, when the arterioles are constricted, they are transformed into stiff and narrow vessels, thereby, stirring the level of blood pressure. As a result, when ARB drugs act on angiotensin II, it blocks the actions of angiotensin II on the arterioles, a situation that gives ARB drugs ability to prevent the effect of angiotensin II of narrowing (constricting) on the arterioles [5]. ARBs have become effective among patients who find it difficult to tolerate an ACE inhibitor, although ARBs have been found to be least equivalent to ACE inhibitors [5]. Studies that have been conducted indicate that benefits of ARBs on cardiovascular morbidity and mortality is extremely close to that of ACE inhibitors, and some studies have established that ACE inhibitors remain the most preferred as first-line therapy in patients with heart failure [6]. Nevertheless, ARBs have become the best alternatives to ACE inhibitors due to their high level of tolerance, cost factor and the ability to substitute ACE inhibitors effectively [6]. Furthermore, it has to be noted that ARBs should be prescribed to patients who demonstrate high intolerance level to ACE inhibitors due to the cough or angioedema as side effects. Besides, the essence of combining ACE inhibitors and ARBs remains a controversial debate and no clear formal consensus has been achieved [4,8]. Theory guiding design, methodology and analysis of clinical trial data Antihypertensive medicines such as ACE inhibitors and ARBs play an important role in treatment of cardiovascular diseases. Specifically, the drugs have to act on the renin-angiotensin system. Basically, adoption of appropriate drugs relies on evidence-based studies of multiple clinical trials that provide opportunity to identify clinical-tested drugs that are efficacious in the treatment of identified diseases. Therefore, analysis of results from clinical trials constitutes an important step towards selecting appropriate medicines. The basic theory in the process of design, methodology and analysis of clinical trial data postulate that the entire process has to evaluate the safety and efficacy of drugs and therapeutic procedures using human subjects (9). As a result, there is always need to understand the principles behind clinical trials in order to achieve and appreciate validity and reliability of the results. As it can be evidenced, reliability and validity of clinical results is the primary ground upon which to deduce whether certain and specific clinical trial tests are efficacious in treatment of diseases. Efficacious of clinical test trials should be premised on the need to achieve reliability and validity of trials through minimisation of bias in all situations and at all levels (10). In other words, maximum adherence to the clinical test trials have to demonstrate aspects of proper inclusion and exclusion criteria, minimisation of bias, Kaplan-Meier plots, hazards ratios and bias. An appropriate inclusion and exclusion criterion reduces variability and distortion, thereby increasing reliability and validity of results (10). At the same time, efficacy of clinical trial tests can be explained by the survival analysis generated from the studies. In this way, Kaplan-Meier plots are appropriate summarizing survival analysis data to establish whether a clinical test trial is efficacious (11). Hazards ratios and bias constitute other aspects that should be observed in review of clinical tests trials. Bias can originate from diverse sources, and it is important that evaluation is made to establish how bias affects reliability and validity of the study. It has been established that reduction of bias and realisation of stronger evidence in clinical tests trials require use of randomisation and use of contemporaneous control groups (12). Besides, it requires the use of prospective rather than retrospective studies, use of larger samples in studies to demonstrate statistical significance as well as clinical significance and use of blinding methods (12). Efficacy of ACEI and ARBs in the treatment of myocardial infarction ACEI and ARBs have been established to be equally efficacious in minimising the mortality after myocardial infarction (MI) [13]. Both ACEI and ARBs have been found to target RAA system and in many instances they have been considered to be equivalent. But, this consideration of equivalence is not appropriate. Analysis of exemplar clinical trial Kenneth Dickstein, John Kjekshus, together with OPTIMAAL Steering Committee, conducted an OPTIMAAL randomised trial. The aim of the randomised trial was to establish the effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction. The nature of study was a multicentre, randomised trial test, and the hypothesis to be tested was that the angiotensin II antagonist losartan would be superior or non-inferior to the ACE inhibitor captopril in decreasing all-cause mortality in high-risk patients after acute myocardial infarction (12). Research methodology involved participation of 5477 patients, aged 50 years and above, where means age was 67.4 years. The selection criteria only included patients who were found to have acute myocardial infarction and heart failure largely during the acute phase or reinfarction. The patients were selected from 329 centres located in seven countries in Europe. Patients were later randomly assigned and titrated to a target dose of losartan (50 mg each day) or captopril (50 mg three times each day) (12). Administration of doses was in line with toleration ability of patients. The basic endpoint was all-cause mortality, and analysis included intention to treat. Findings from the randomised trial indicated that 946 deaths were realised during a mean follow-up of 2.7 (0.9) years. This included 499 deaths, representing 18 per cent, for the losartan group of patients, and 447 deaths, representing 16 percent, for the captopril group of patients (12). Further analysis of data showed that losartan was significantly better tolerated than captopril, where smaller number of patients discounted study medication. At the end of the study, interpretation made was that there was no significant difference in total mortality in favour of captopril (12). As a result, it was concluded that ACE inhibitors should remain first-choice treatment in patients after complicated acute myocardial infarction. Therefore, losartan could not be recommended in the population. Nevertheless, losartan was found to be more tolerated than captopril and at same time was associated with fewer discontinuations. Design, methodology and analysis Jong, Demers, McKelvie, Liu (2002) conducted a meta-analysis study of all randomized controlled trials [14]. The trials compared ARBs with either placebo or ACEIs among patients who demonstrated symptomatic heart failure (HF). The primary objective of the study was to establish the impact ARBs have on mortality and hospitalization, especially among patients with HF [14]. A total of 17 trials were conducted that involved 12,469 patients. The authors performed a systematic search for almost all randomized controlled trials that had been conducted and published between 1966 and May 2001. The notable databases the authors obtained the materials included MEDLINE, ENBASE, Biological Abstract, International Pharmaceutical Abstract, Cochrane Controlled Trials Database, McMaster Cardiovascular Randomised Clinical Trial Registry and Science Citation Index [14]. Results of the meta-analysis study, conducted within 95% confidence level, indicated that ARBs were inferior to controls in the pooled rates of death; 0.96; 0.75 to 1.23 and hospitalization at 0.86; 0.69 to 1.06 [10]. Another analysis, stratified analysis, showed lack of significant differences with regard to benefits of ARBs over placebo especially in reducing mortality and hospitalisation. The scores obtained were 0.68; 0.38 to 1.22 for reducing mortality and 0.67; 0.29 to 1.51 for hospitalisation [14]. The scores obtained in stratified analysis were similar to ARBs administered in absence of background ACEI therapy. Furthermore, when compared with ACEIs, ARBs were found to be inferior, especially in reducing mortality (1.09; 0.92 to 1.22) and hospitalisation (0.95; 0.80 to 1.13) [10]. Besides, when ARBs were paired with ACEIs, it was established that ARBs only appeared superior to ACEIs alone in reducing hospitalisation (0.74; 0.64 to 0.86) and not mortality rate (1.04; 0.91 to 1.20) [14]. The conclusion derived from the meta-analysis study showed that ARBs when compared to ACEIs cannot be regarded to be superior in reducing all-cause mortality or hospitalisation of heart failure patients. Nevertheless, when ARBs are used as monotherapy, when ACEIs are not present, or when used as a combined therapy with ACEIs, results appear to be promising. The trial results generated using almost similar research methodology as that of exemplar clinical trial, can be used to justify the fact that ACE inhibitors should remain first-choice treatment in patients after complicated acute myocardial infarction. Another meta-analysis study was carried out in 2004 by a group of authors [15]. The meta-analysis include 24-randomised, double-blind and controlled trials. In total, 38,080 patients were involved in the study, where majority were from New York Heart Association class II to IV with heart failure. Data collected by authors was categorised into three primary comparison groups: ARBs versus placebo, ARBs versus ACEIs and combination of ARB and ACEIs versus ACEIs [15]. Results for patients with high-risk acute myocardial infarction (MI) showed that no difference was established in all-cause mortality or hospitalisation of heart failure in the two randomised trials. Therefore, conclusion arrived by the authors was that since no difference was established between the drug classes in efficacy for minimising all-cause mortality and heart failure hospitalisation, ACE inhibitors remain the first-choice in treating high-risk acute MI, although ARBs can be alternatives due to their less side effects [15]. Conclusion Numerous clinical trials that explain and evaluate the use of ACEIs and ARBs in myocardial infarction (MI) patients and in other special populations exist today. It has been found out that ACEIs and ARBs tend to have other benefits other than the usual blood pressure-lowering impact, especially when used in specific populations. Comparative analysis of clinical trials that currently exist regarding the efficacy of ARBs and ACEIs show that ARBs and ACEIs tend to exhibit no difference in basic outcomes. At the same time, the level of side effects between the two drugs has been found to differ slightly with trial results showing ARBs to be better tolerated as compared to ACEIs. Given that ACEIs remain first-choice in treating cardiovascular diseases, results from clinical trials show that ARBs can be used as appropriate alternatives, especially as the cost factors become critical in the entire process of treating and managing cardiovascular disease. Besides, the clinical trials indicate that in future, the use of ACEIs or ARBs in treatment of MI or any other cardiovascular diseases may largely depend on patient-specific factors, a situation that makes the use of ARBs as alternatives to ACEIs inevitable. References 1. McKay, GA, Reid, JL, Walters, MR. Lecture Notes: Clinical Pharmacology and Therapeutics. 8th ed. West Sussex: John Wiley & Sons; 2011. 2. Becker, S, Flaws, B, Casarias, R. The Treatment of Cardiovascular Diseases with Chinese Medicine: A Textbook and Clinical Manual. 1 st ed. Boulder: Blue Poppy Enterprises, Inc.; 2005. 3. Poole, VA, Peterson, AM. Pharmacotherapeutics for Advanced Practice: A Practical Approach. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2005. 4. Henderson, KE, Baranski, TJ, Bickel, PE, Clutter, WE, McGill, JB. The Washington Manual® Endocrinology Subspecialty Consult. 2 nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008. 5. Woodrow, R, Colbert, BJ, Smith, DM. 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Meta-analysis: Angiotensin-receptor Blockers in Chronic Heart Failure and High-risk Acute Myocardial Infarction. Annals of Internal Medicine. 2004 November 2; 141(9): 693-704. 16. Ma, TK, Kam, KH, Yan, BP, Lam, YY. Renin-Angiotensin-Aldosterone System Blockade for Cardiovascular Diseases: Current Status. British Journal of Pharmacology. 2010; 160: 1273-1292. Read More