Disease management constitutes an important area in the clinical research where drugs possess a significant position. The effect of drugs on various organ systems has been the area of much research interest which gradually made feasible the development of several classes of drugs. Drugs may have dual role of promoting and inhibiting the vital biochemical and molecular pathways that play influential role in the disease outcome.
Angiotensin converting enzyme (ACE) inhibitors are considered as anticongestive heart failure and antihypertensive agents. They have gained wide spread physician and patient satisfaction. The ACE inhibitors prevent the angiotensin II development in tissues and blood and ultimately reduce blood pressure and systemic vascular resistance. This enables the cardiac function improvement without altering the brain, heart and kidney vital functions.
1 Briefly, ACE inhibitors prevent the formation of active vasoconstrictor angiotensin II from
Angiotensin I. The hormone angiotensin II is responsible for stimulation of aldosterone, retention of high water and sodium. The ACE inhibitors are efficacious and are similar to beta-blockers and diuretics which are recommended for the treatment of renovascular hypertension. They enhance cardiac output and stroke volume and enable left ventricular hypertrophy regression. ACE inhibitors serve as antihypertensive agents when they are combined with diuretic drugs.3
The other class of drugs worth discussing is angiotensin receptor antagonists. Angiotensis are peptide hormones obtained from angiotensinogen, a protein precursor. This is due to proteolytic enzyme catalytic action. Angiotensin II is the main effector of rennin- angiotensin system. It serves as a vasoconstrictor.
Angiotensin I and II are important for the rennin angiotensis system. Here, angiotensin I is formed by the action of rennin on Angiotensinogen. Subsequently, angiotensin I is converted to angiotensin I by the action of ACE.4
Two subtypes of receptors are described to bind angiotensin II. These are AT1 and AT2 receptor antagonists. These receptors are polypeptides that contain 350 amino acids that extend over the cell membrane. Functionally, AT1 and AT2 receptors are distinct.5
The receptors of AT1 are susceptible to desensitization and rapid internalization when they are stimulated by agonists while receptors of AT2 are not susceptible.
Most importantly, with regard to the hypertension pathohysiology, angiotensin II efficacy is more accomplished with AT1 receptor where a cardiacvascular and renal system become remodeled.6
Courtesy: Guo Deng and his associates6
Next, the therapeutic efficacy of ACE inhibhitors and Angiotensin receptor antagonists is important to understand with regard to their relevance in heart failure and the associated complications like hypertension.
Briefly, heart failure is reported to result from a series of events like dysfunction of left ventricular systole, activation of neurohormones and ventricular remodeling. As such, sympathetic nervous systems and renin-angiotensin-aldosterone become stimulated in patients with overt heart failure and as well those in left ventricular systolic dysfunction prone patients. This leads to fibroblast growth, myocyte necrosis, myocyte hypertrophy and cell death. Therefore, therapeutic agents are necessary that provide relief from adverse symptoms, and reduce and weaken ventricular remodeling and progressive heart failure in patients. This situation has demanded the interference of ACE inhibitors and angiotensinII receptor blockers.7
ACE inhibitors are reported to be reliable in treating myocardial Infarction (MI). Some of the emerging agents described to play role are ramipril, quinapril, perindopril, pentopril, moexipril, spirapril, temocapril, cilazapril and benazepril. In order to become active pharmacological metabolites, these agents must possess carboxy functional groups and need hepatic stimulation. These agents exhibit either flat or linear dose reponse curves and reach optimum plasma concentrations at t(max) level.Cerain agents like moexipril and imidapril need low dose administration.8
Angiotensin II receptor blockers (ARBs) offer a novel category of antihypertensive agents. They exhibit variation from ACE inhibitors in their mode of action and tend to fill the gaps of ACE’ inhibhitors. This is because ACE inhibition competitively may contribute to rennin and angiotensin I level production increasingly which subsides the blocking action.ACE inhibition was described to occur non specifically and this leads to accumulation of achykinins, bradykinin in addition to angiotensin I, and finally a non significant angiotensin II production occurs. Finally, these events are not affected by ACE inhibition.9
It was described that the therapeutic action of angiotensin II-receptor blockers (ARBs) was mainly associated with the selective binding to angiotensin type 1 receptors by agents. Thus AT1 receptor blockage is very important.10
In an experiemtnal study, the therapeutic role of AT1 receptors was better described
with regard to TNF-alpha. This is because in Myocardial infarction (MI),TNF-alpha was shown to participate in cardiac contractile dysfunction. As Angiotensin II type 1 (AT1) receptor plays role duringTNF-alpha synthesis, treatment with an AT1 receptor blocker named irbesartan inhibited TNF-alpha production which lead to an improvement in cardiac function.
This has indicated that AT1 receptor blockade prevents post-infarct cardiac TNF-alpha production. Subsequently, myocardial alterations followed up for 7 days after MI were diminished.11 This has supported an earlier description where angiotensin II (AngII) type 1 receptor (AT1R) blockers (ARBs) has been shown to be efficacious. Here, ARBs irbesartan and valsartan have limited the development of certain cardiac events like increased left atrial pressure, left ventricular dP/dtmin, dP/dtmax, infarct size infarct expansion and thinning, ejection fraction and diastolic function. In addition, the postischemic reperfused zone was foundwith enhanced AT2R protein expression and mo AT1 R protein variations. Hence, AT1R blockade and the resulting AT2R protein expression upregualtion was demonstrated to limit myocardial injury. This has strengthened the cardioprotective effects of ARBs during RMI episodes.
It was suggested that ARBs therapeutic role should be assessed in patients with acute coronary syndromes especially those who have undergone reperfusion therapy.12
Myocardial infarction is a serious problem. It encompasses a spectrum of complications That include Left ventricular dysfunction (LVD), congestive heart failure (CHF) and ischaemic heart disease or coronary artery narrowing. It is also associated with hypertension and cardiomyopathy.13 It is important to mention that various studies have concentrated their research in retrieving data and conducting clinical trials to compare the efficacy of ACE inhibitors and angiotensin receptor blockers (ARB’s).
Earlier, clinical trials conducted on patients have focused on adverse effects and mortality. They revealed that the two drug agents have role in contributing to hypotension, renal failure and hyperkalemia. Actually, myocardial infarction patients with recent episodes did not differ in the mortality when ACE inhibitor, captopril and angiotensin II receptor antagonist (losartan or valsartan) were given. The study emphasized that a placebo controlled randomised trials is also important to better assess the angiotensin II receptor antagonists effect if mortality is under investigation while comparing angiotensin II receptor antagonist with an ACE inhibitor.14 This data has supported a randomized clinical study known as Valsartan in Acute Myocardial Infarction Trial (VALIANT). Here nearly, 14,703 patients with heart failure were studied for assessing the effects of two agents. But, there was a poor outcome in elderly patients after receiving both the agents and it suggested the use of with heart failure, beta-blockers and aspirin.15 More importantly, in a retrospective closed cohort study on 14,190 older patients, after myocardial infarction patients using ARB possessed similar 1-year mortality as seen with ACEI usage in daily care patients .
Both agents appear efficacious but ARBs are proven to be more costlier.16 In high risk patients with cardiovscualr disease complications, a comparison trial study known as ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized AssessmeNt Study in ACE iNtolerant was initiated to assess both the agents protective ability on blood pressure. The patients who are old are found on lipid-lowering therapy andof beta-blockers.17 This has indicated that patients with heart failure, especially elderly are more prone to beta-blocker usage. However, treatment with either only ACE inhibitor or ARB although has shown benefits in some trials, the effectiveness of combined therapy still needs further data.18 In few studies, where data from 1966 to August 2004 was reviewed, ARB’s have not proven to be significant in reducing MI and death compared to ACE inhibitors. Instead they were given a second-line alternative option after ACE inhibitors.19
There were few concerns with regard to the risks contributed by the combination therapy and monotheray alone. To address this, a nine trial data of patients revealed that combination therapy of ACEI+ARB has an increased risk of side effects that may lead to their discontinuity when compared with only ACE. This has suggested that the addition of ARBs to ACEs should be avoided on a routine basis and such strategy also needs adverse effect monitoring.20 Angiotensin II receptor blockers appear to offer more protection than that of their counterparts ACE’s especially when the risk of stroke is assessed although both agents are efficacious in reducing MI and adverse cardiovascular events, as revelae from a meta-analysis of randomized comparative trials.21 Recently, a large study was conducted by Agency for Healthcare Research and
Quality (AHRQ) in assessing the comparative effectiveness of ACE and ARB’s. It revealed that ACE inhibitors are significant in lowering the risks of myocardial infarction (MI) an adverse cardiovascular events and total mortality. However, there were withdrawal cases due to hyperkalemia, cough and syncope. In one trial of TRANSCEND, there was no significant difference found among the cardiovascular events and in one trial of ONTARGET, both agents exhibited similar effects in terms of efficacy but combination therapy resulted in increased number of total study discontinuations because of syncope and hypotension. This indicated that the efficacy of ACE and ARBs may vary among different patient subpopulations.22 Therefore, it was strongly emphasized by research groups that in order to better understand the efficacy of ACE and ARB’s, there is need to understand characteristics of patient at the individual level and recommend patients for ACE/ARB usage who may become beneficial. 23
Next ,the clinical trials to be conducted to study the efficacy of ACEs and ARB’s in patients with MI and the associated cardiovascular adverse events requires a basic inclusion / exclusion criteria .This is done for recruiting the eligible patient population and removing the ineligible ones.
With regard to ONTARGET and TRANSCEND trials the inclusion criteria is that the patient age should be more than 55 years of age They should possess Coronary artery disease complications like previous acute myocardial infarction which should be greater than 2 days after uncomplicated AMI, Stable angina, Unstable angina ( greater than 30 days before + confirmed coronary artery disease CAD with document evidence), Peripheral artery disease; Limb/foot amputation, previous limb vascular surgery or angioplasty, Significant peripheral vascular stenosis by angiography in a proportion of greater than 50%, Diabetes mellitus- patient with confirmed end organ damage and at high risk.24 The exclusion criteria involves
Use of medication; patient fails or exhibits inability to discontinue ACEi or ARB, has known ACEi or ARB, intolerance or hypersensitivity, Cardiovascular disease events like
pericardial constriction significant valvular heart disease, Syncopal episodes of unknown aetiology and stroke due to subarachnoid hemorrhage, symptomatic heart failure and heart transplant recipients. Other excluding criteria is hepatic dysfunction and hypotension.24
In clinical trial experiments, results are linked with a statistical component known as ‘Bias’ It constitutes the effect of parameters or factors like experimental methodology or design, methods chosen for carrying out experiments their analysis and interpretation.
Bias minimization is feasible by randomization and blinding. Randomization is of the following types. In simple randomization, patients are chosen a specific treatment agent like A or B. This is determined by a strategy of rolling a fair die or tossing a coin where heads and tails represent A and B respectively.25 In weighted randomization, the patient or sample size to be given treatment A is roughly a double figure of patients to be given treatment B.26 In block randomization, the patients who are participating in different treatment groups are balanced to a very close figure.27,28
In stratified randomization, the desired or selected patient factor in one treatment group is made similar with other treatment group. Say for example, this randomization assures equal age characteristics in patients of different groups. 29 Similarly, minimization is an approach that guarantees a fine balance of factors or patient characteristics in samples between groups.26
Next, blinding involves the hiding or masking of details say, of a particular treatment agent. It may be single blinded, when the researcher only knows the treatment given to the patient, and is double blind when both the researcher and patient become unknown to the treatment type or agent.30 It is important to note that the studies mentioned in this description are of randomized clinical trials intended to minimize bias.
Finally, statistical curves play important role in interpretation. For example, Kaplan Meier curves, survival probabilities can be depicted. In an ONTARGET study, Kaplan Meier curves were used and it was inferred that the curves for death outcome resulting from cardiovascular causes, myocardial infarction, stroke etc did not show significant variation between combination treatment and the telmisartan, ramipril groups.32
Hazard ratios also reflect survival data. To say, they analyze the practicability a hypothesis made before the study. Once the results were obtained, the researcher attempts to evaluate what might be the causative agent or factor.33
In a study mentioned earlier in this description, hazard ratios were used to determine the 1-year mortality occurrence hen compared between ACE and ARB use after myocardial infarction.16
In view of the above information, it can be concluded that ACE’s and ARB’s are potent therapeutic agents with proven efficacy. A large number of clinical trial data has compared the effectiveness of these agents and revealed the importance of monotherapy, combination therapy in different patient population under various circumstances and further indicating the need for a tailored medical attention. Adverse reactions and the benefits offered by these agents need to be thoroughly evaluated in an evidence based manner.
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