Intraclass differences among antihypertensive drugs.

The four major classes of antihypertensive drugs­diuretics, ß-blockers, calcium channel blockers, and renin-angiotensin system inhibitors (including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers)­have significant qualitative and quantitative differences in the adverse effects they cause. Structural and chemical differences have been identified within these classes, especially among the calcium channel blockers and, to a lesser extent, among the thiazide/thiazide-like diuretics. However, it has been more difficult to demonstrate that these differences translate into differential effects with respect to either the surrogate endpoint of blood pressure reduction or, more importantly, hypertension-related cardiovascular complications. Based on a hierarchy-of-evidence approach, differences are apparent between hydrochlorothiazide and chlorthalidone based on evidence of moderate quality. Low-quality evidence suggests atenolol is less effective than other ß-blockers. However, no significant intraclass differences have been established among the other classes of antihypertensive drugs.

Angiotensin converting enzyme inhibitor-related angioedema: onset, presentation, and management.

OBJECTIVE: This study aimed to determine the duration of use, presentation, and management of angiotensin converting enzyme (ACE) inhibitor-related angioedema patients at an urban academic medical center. METHODS: Retrospective chart review. RESULTS: Eighty-eight patients who presented with ACE inhibitor-related angioedema between January 1, 2012, and December 31, 2012, were identified. They presented anywhere from 1 day to 20 years after starting an ACE inhibitor. About half the patients (50.7%) presented after taking an ACE inhibitor for at least 1 year. Fifty-five patients were female (62.5%). Twenty-eight patients (31.8%) had an airway intervention with 27 intubated and 1 requiring cricothyroidotomy. Six patients were intubated after more than 1 flexible laryngoscopy. The percentage of patients with involvement of the face, lips, tongue, floor of mouth, soft palate/uvula, and larynx were 12.5%, 60.2%, 39.7%, 6.8%, 17.0%, and 29.5%, respectively. Sixty-eight percent of patients with laryngeal edema were intubated. The majority of patients were treated with a corticosteroid and H1 and H2 receptor antagonists. CONCLUSION: Angioedema can occur at any time after starting ACE inhibitor use, with nearly half occurring after 1 year of use. Laryngeal involvement occurred in a minority of patients, but most of these patients were felt to require airway protection.

Meta-analysis: impact of drug class on adherence to antihypertensives.

BACKGROUND: Observational studies suggest that there are differences in adherence to antihypertensive medications in different classes. Our objective was to quantify the association between antihypertensive drug class and adherence in clinical settings. METHODS AND RESULTS: Studies were identified through a systematic search of English-language articles published from the inception of computerized databases until February 1, 2009. Studies were included if they measured adherence to antihypertensives using medication refill data and contained sufficient data to calculate a measure of relative risk of adherence and its variance. An inverse-variance-weighted random-effects model was used to pool results. Hazard ratios (HRs) and odds ratios were pooled separately, and HRs were selected as the primary outcome. Seventeen studies met inclusion criteria. The pooled mean adherence by drug class ranged from 28% for ß-blockers to 65% for angiotensin II receptor blockers. There was better adherence to angiotensin II receptor blockers compared with angiotensin-converting enzyme inhibitors (HR, 1.33; 95% confidence interval, 1.13 to 1.57), calcium channel blockers (HR, 1.57; 95% confidence interval, 1.38 to 1.79), diuretics (HR, 1.95; 95% confidence interval, 1.73 to 2.20), and ß-blockers (HR, 2.09; 95% confidence interval, 1.14 to 3.85). Conversely, there was lower adherence to diuretics compared with the other drug classes. The same pattern was present when studies that used odds ratios were pooled. After publication bias was accounted for, there were no longer significant differences in adherence between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors or between diuretics and ß-blockers. CONCLUSION: In clinical settings, there are important differences in adherence to antihypertensives in separate classes, with lowest adherence to diuretics and ß-blockers and highest adherence to angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. However, adherence was suboptimal regardless of drug class.

Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management.

BACKGROUND: Population-based data on the demographics and clinical characteristics of patients with multiple unrelated drug class intolerances noted in their medical records are lacking. OBJECTIVES: To provide population-based drug "allergy" incidence rates and prevalence, and to identify individuals with multiple drug intolerance syndrome (MDIS) defined by 3 or more unrelated drug class "allergies," and to provide demographic and clinical information on MDIS cases. METHODS: Electronic medical record data from 2,375,424 Kaiser Permanente Southern California health plan members who had a health care visit and at least 11 months of health care coverage during 2009 were reviewed. Population-based drug "allergy" incidence rates and prevalence were determined for 23 unrelated medication classes. RESULTS: On January 1, 2009, 478,283 (20.1%) health plan members had at least one reported "allergy." Individuals with a history of at least 1 "allergy" and females, in general, reported higher population-based new "allergy" incidence rates. Multiple drug intolerance syndrome was present in 49,582 (2.1%). The MDIS cases were significantly older, 62.4 ± 16.1 years; heavier, body mass index 29.3 ± 7.1; and likely to be female, 84.9%, compared with average health plan members. They had high rates of health care utilization, medication usage, and new drug "allergy" incidence. They sought medical attention for common nonmorbid conditions. CONCLUSIONS: Multiple drug intolerance syndrome is in part iatrogenic. It is associated with overweight elderly women who have high rates of health care and medication usage. Urticarial syndromes only explain a small fraction of MDIS cases. Multiple drug intolerance syndrome is associated with anxiety, but not predominately with immunoglobulin E (IgE)-mediated allergy or life-threatening illness. Multiple drug intolerance syndrome can be managed by medication avoidance and judicious rechallenge.

The effect of perindopril and enalapril on plasma resistin levels in normotensive patients with coronary heart disease.

INTRODUCTION: It has been suggested that adipose tissue hormones are involved in the mechanism of action of angiotensin-converting enzyme (ACE) inhibitors. Very little is known as to whether the action on resistin contributes to the clinical effectiveness associated with the use of these agents. MATERIAL AND METHODS: The aim of this study was to compare the effects of plasma- and tissue-type ACE inhibitors (enalapril and perindopril) on plasma resistin content in coronary artery disease (CAD) individuals without arterial hypertension. The samples used in our analysis were obtained at baseline, and again after 30 and 90 days of treatment, from 22 patients receiving enalapril (20 mg/d), 24 receiving perindopril (4 mg/d), 20 receiving no angiotensin-converting enzyme inhibitors, and 20 healthy subjects. Each group consisted of patients sensitive and resistant to insulin. RESULTS: Plasma resistin content was higher in normotensive CAD patients, particularly in the subgroup with reduced insulin sensitivity, than in the control group. Both ACE inhibitors produced a weak effect on blood pressure. Perindopril treatment reduced resistin levels, while enalapril only tended to decrease its content. The effect of perindopril was stronger in insulin-resistant than in insulin-sensitive subjects. CONCLUSIONS: Our results demonstrate the superiority of perindopril over enalapril in reducing plasma resistin levels, particularly in insulin-resistant subjects. They justify the choice of a tissue-type ACE inhibitor in normotensive CAD individuals, requiring administration of this group of agents.

A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension.

Cardiovascular diseases (CVDs) have become the leading cause of disability and death worldwide, particularly in low- and middle-income countries. Hypertension, a major cause of CVD progression, is widely attributable to genetic, behavioral, and environmental risk factors. Among the genetic reasons, angiotensin II enzyme, produced as a result of abnormal functioning of the renin⁻angiotensin system, is reported as the foremost cause of hypertension. A cascade of genes, including those encoding for WNK kinases (WNK1 and WNK4), Bp1, Bp2, angiotensinogen, and other enzymes, is involved in the conversion of angiotensin I to angiotensin II. However, the angiotensin-converting enzyme (ACE) plays a crucial role in this pathway. Therefore, ACE could be a potential therapeutic target in regulating the conversion of angiotensin I to angiotensin II and eventually controlling hypertension. In this study, a molecular docking-based approach was utilized for identifying and evaluating potential inhibitors of ACE present in herbs, other natural sources, and synthetic sources, on the basis of these compounds' binding affinities and other physicochemical features. In addition, the suitability of these inhibitors as drugs for biological systems, considering their adsorption, distribution, metabolism, and excretion (ADME), was predicted using Lipinski's rule. In conclusion, our study provides a novel and clearer insight into the interaction properties of known putative inhibitors of ACE.

Do ACE inhibitors all provide the same outcomes benefits in high-risk cardiovascular patients?

The Heart Outcomes Prevention (HOPE) trial was the first to demonstrate the benefits of the angiotensin-converting enzyme (ACE) inhibitor ramipril for high-risk cardiovascular patients. Whether the cardioprotective effects seen in HOPE and other trials are specific to distinct ACE inhibitors remains controversial. Evidence of a lack of class effect for ACE inhibitors has policy and financial implications related to reference pricing by insurers and inclusion on pharmacy formularies. Because head-to-head trials comparing the different ACE inhibitors are unforeseen, clinicians and administrators must rely on secondary-level data and observational studies. Only a handful of studies have sought to address the dispute over a class effect among ACE inhibitors, which is reviewed in this article.

Modeling dipeptides as ACE inhibitors and bitter-tasting compounds by means of E-state structure-information representation.

Topological Structure-Information Representation (SIR) serves as the basis for QSAR model development on two data sets of dipeptides. Data sets of both bitter-taste (48 compounds) and angiotensin-converting-enzyme (ACE) inhibition (58 compounds) were analyzed by means of multiple linear-regression methods to produce QSAR models that relate structure to property. For the bitter-taste data set, two variables describe the data well, both being whole-molecule descriptors: (1)chi(v) (molecular connectivity first-order valence index) and SHBa (sum of E-State indices for H-bond acceptors) yield r(2)=0.88, s=0.22. External validation and cross-validation indicate that the model may be predictive. For the ACE-inhibition data set, five variables produced a satisfactory model. Four of the descriptors relate to amino acid side chains: the E-State polarity/non-polarity index Q(v) (for position A adjacent to the N-terminus; Fig. 1) and the E-State index s(2) (for the backbone position of substitution), along with the square of the molecular connectivity path-four valence index ((4)chi(PC); for side chain B adjacent to C-terminus) and the E-State index s(5) (for the attachment point of the side chain B (Fig. 1)). Together with the E-State whole-molecule descriptor for internal H-bonding (five skeletal bonds; SHBint5), the five variables form a predictive model (r(2)=0.88, s=0.36). Both external-test and cross-validation-test statistics indicate that the model may be predictive. This study is the first investigation in which E-State descriptors are developed for amino acid side chains.

The landscape after PEACE: do all ACE inhibitors act in an identical way?

The results of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE trial), involving patients with stable coronary heart disease, demonstrated that the angiotensin-converting enzyme (ACE) inhibitor trandolapril did not reduce cardiovascular mortality, or the incidence of fatal or non-fatal myocardial infarction. These results were in conflict with the vast majority of previously published large-scale trials, and could be seen to weaken confidence in ACE inhibitor therapy of ischaemic heart disease. This review article examines the results of PEACE in comparison with the other major trials in terms of the severity of the disease in the patients, the statistical power of the analyses, the doses of the agents used and the concept of a 'class effect' of the ACE inhibitors.

Antithrombotic effect of tissue and plasma type angiotensin converting enzyme inhibitors in experimental thrombosis in rats.

This study compared the antithrombotic effect of plasma angiotensin converting enzyme inhibitors (ACE-Is): captopril (CAP), enalapril (ENA) and tissue ACE-Is: perindopril (PER), quinapril (QUIN) in experimental venous and arterial thrombosis. Normotensive Wistar rats were treated p.o. with CAP (75 mg/kg), ENA (20 mg/kg), PER (2 mg/kg) and QUIN (3 mg/kg) for 10 days. The influence of ACE-Is on coagulation and fibrinolytic systems as well as platelet function was evaluated. The hypotensive effect of ACE-Is was equal in all groups. QUIN maintained the final carotid blood flow at the highest value in comparison to PER and plasma ACE-Is. The arterial thrombus weight was reduced in PER and QUIN groups while venous thrombus weight was also reduced after CAP. Tissue and plasma ACE-Is caused the inhibition of platelet adhesion and aggregation. A reduction of fibrin generation, prolongation of prothrombin time (PT), activated partial thromboplastin time (APTT) and shortening of euglobulin clot lysis time (ECLT) were observed after PER and QUIN treatment. In conclusion, given in equipotent hypotensive doses, tissue ACE-Is exerted more pronounced antithrombotic effect than plasma ACE-Is in experimental thrombosis. The differences between tissue and plasma ACE-Is in terms of their more pronounced inhibition of experimental thrombosis may be related to the intensified activation of fibrinolysis and inhibition of coagulation.

Medication adherence and persistence according to different antihypertensive drug classes: A retrospective cohort study of 255,500 patients.

BACKGROUND: Suboptimal adherence to antihypertensives leads to adverse clinical outcomes. This study aims to determine and compare medication adherence and persistence to different first-line antihypertensive drug classes in a large cohort. METHODS: A cohort study was performed using claims data for prescriptions in the German statutory health insurance scheme that insures approximately 90% of the population. A total of 255,500 patients with a first prescription of an antihypertensive were included and followed for 24months. Persistence was determined based on gaps in continuous dispensation. Adherence was analyzed by calculating the medication possession ratio (MPR). RESULTS: Within a 2-year period, 79.3% of all incident users of antihypertensive monotherapy met the classification of non-persistence (gap >0.5 times the number of days supplied with medication) and 56.3% of non-adherence (MPR<0.8). Beta-blockers (42.5%) and angiotensin-converting enzyme inhibitors (31.9%) were the most widely prescribed drug classes. Non-persistence and non-adherence were highest for diuretics (85.4%, n=6149 and 66.3%, n=4774) and lowest for beta-blockers (77.6%, n=76,729 and 55.2%, n=54,559). The first gap of antihypertensive medication occurred in median 160-250days after initiation, and the average medication possession ratio for all drug classes was less than 0.8. Fixed combinations with diuretics showed a 19.8% lower chance for non-adherence (OR=0.802, 99.9% CI=[0.715-0.900], p<0.001) and an 8.4% lower hazard for non-persistence (HR 0.916, 99.9% CI=[0.863-0.973], p<0.001) compared with monotherapies. CONCLUSIONS: This large cohort study reveals important differences in 2-year adherence and persistence between antihypertensives that were lowest for diuretics. Fixed-dose combinations with diuretics may facilitate adherence compared to single substance products. However, effective strategies to improve adherence to antihypertensives are needed regardless of drug class.

Comparison of angiotensin-converting enzyme inhibitors in the treatment of congestive heart failure.

The effectiveness of the different angiotensin-converting enzyme (ACE) inhibitors in the treatment of patients with congestive heart failure (CHF) was compared by performing a retrospective cohort study using linked administrative databases on elderly patients admitted to the hospital for the treatment of CHF. Relative to those initiated on enalapril, no significant differences in the combined end point of readmission to the hospital for CHF or mortality were observed among users of lisinopril, ramipril, or other ACE inhibitors. In terms of effectiveness for the treatment of patients with CHF, the findings of this study suggest a class effect among ACE inhibitors.

Efficacy of different drug classes used to initiate antihypertensive treatment in black subjects: results of a randomized trial in Johannesburg, South Africa.

BACKGROUND: Thiazides are recommended to initiate antihypertensive drug treatment in black subjects. OBJECTIVE: To test the efficacy of this recommendation in a South African black cohort. METHODS: Men and women (N = 409), aged 18 to 70 years, with a mean ambulatory daytime diastolic blood pressure between 90 and 114 mm Hg, were randomized to 13 months of open-label treatment starting with the nifedipine gastrointestinal therapeutic system (30 mg/d, n = 233), sustained-release verapamil hydrochloride (240 mg/d, n = 58), hydrochlorothiazide (12.5 mg/d, n = 58), or enalapril maleate (10 mg/d, n = 60). If the target of reducing daytime diastolic blood pressure below 90 mm Hg was not attained, the first-line drugs were titrated up and after 2 months other medications were added to the regimen. RESULTS: While receiving monotherapy (2 months, n = 366), the patients' systolic and diastolic decreases in daytime blood pressure averaged 22/14 mm Hg for nifedipine, 17/11 mm Hg for verapamil, 12/8 mm Hg for hydrochlorothiazide, and 5/3 mm Hg for enalapril. At 2 months the blood pressure of more patients treated with nifedipine was controlled: 133 (63.3%, P

Heart Failure Medications Detection and Prescription Status Classification in Clinical Narrative Documents.

Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin II Receptor Blockers (ARB) are two common medication classes used for heart failure treatment. The ADAHF (Automated Data Acquisition for Heart Failure) project aimed at automatically extracting heart failure treatment performance metrics from clinical narrative documents, and these medications are an important component of the performance metrics. We developed two different systems to detect these medications, rule-based and machine learning-based. The rule-based system used dictionary lookups with fuzzy string searching and showed successful performance even if our corpus contains various misspelled medications. The machine learning-based system uses lexical and morphological features and produced similar results. The best performance was achieved when combining the two methods, reaching 99.3% recall and 98.8% precision. To determine the prescription status of each medication (i.e., active, discontinued, or negative), we implemented a SVM classifier with lexical features and achieved good performance, reaching 95.49% accuracy, in a five-fold cross-validation evaluation.

Different Angiotensin-converting enzyme inhibitors and the associations with overall and cause-specific mortalities in patients with hypertension.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been widely used in the treatment of hypertension, but the comparative effectiveness in reducing mortality among different drugs is seldom reported. METHODS: We identified hypertensive patients who started captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril, or imidapril therapy from Taiwan's National Health Insurance database between 1 January 2004 and 31 December 2009. Overall and cause-specific mortalities were ascertained through a linkage to Taiwan's National Death Registry. Patients were followed from the initiation of ACE inhibitors to death, disenrollment, or study termination (31 December 2010). A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI), using ramipril as the reference group. RESULTS: A total of 989,489 hypertensive patients were included, with a mean follow-up ranging from 3.5 years for imidapril to 4.5 years for enalapril. Captopril initiators had the highest overall mortality rate (117.8 per 1,000,000 person-days) as compared to other ACE inhibitors (54.3-79.4 per 1,000,000 person-days). Patients who started captopril therapy had a significantly increased risk of overall mortality (HR: 1.28, 95% CI: 1.24-1.31) when compared with ramipril. Enalapril (HR: 1.08, 95% CI: 1.05-1.11) and fosinopril (HR: 1.08, 95% CI: 1.05-1.12) were also associated with a modestly increased risk. No difference in mortality was found for lisinopril, perindopril, and imidapril, as compared with ramipril. CONCLUSIONS: There are differences in the mortality risk associated with different ACE inhibitors. However, potential residual confounding effects might still exist.

A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension.

PURPOSE: Antihypertensive medications have different effects on left ventricular mass. We conducted a meta-analysis of double-blind trials that measured the effects of antihypertensive therapy on left ventricular mass. METHODS: Medical databases and review articles were screened for double-blind, randomized controlled trials (through September 2002) that reported the effects of diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor antagonists on echocardiographic left ventricular mass in essential hypertension. Treatment arms of the same drug class, weighted for the number of patients, were combined. Analysis of covariance was performed to detect differences among drug classes in effects on left ventricular structure. RESULTS: Eighty trials with 146 active treatment arms (n = 3767 patients) and 17 placebo arms (n = 346 patients) were identified. Adjusted for treatment duration and change in diastolic blood pressure, there was a significant difference (P = 0.004) among medication classes: left ventricular mass index decreased by 13% with angiotensin II receptor antagonists (95% confidence interval [CI]: 8% to 18%), by 11% with calcium antagonists (95% CI: 9% to 13%), by 10% with ACE inhibitors (95% CI: 8% to 12%), by 8% with diuretics (95% CI: 5% to 10%), and by 6% with beta-blockers (95% CI: 3% to 8%). In pairwise comparisons, angiotensin II receptor antagonists, calcium antagonists, and ACE inhibitors were more effective at reducing left ventricular mass than were beta-blockers (all P <0.05 with Bonferroni correction). CONCLUSIONS: Antihypertensive drug classes have different effects on left ventricular mass reduction. Whether a greater reduction of left ventricular mass results in better clinical outcomes remains to be determined.

Importance of long-acting angiotensin-converting enzyme inhibitors for congestive heart failure.

The renin-angiotensin system (RAS) has both localized and systemic effects in the pathophysiology of heart failure. These may lead to structural changes in the heart and blood vessels as well as to more disseminated symptomatology, including vasoconstriction and both salt and water retention. In association with other neurohormonal mechanisms, such as the sympathetic nervous system, these latter effects result in an elevated work load for the heart. The increase in neurohormonal activity, seen in some patients with heart failure, may result in a loss of circadian variation in heart rate and blood pressure and deprive the heart of a needed reduction in work load during the night. The suppression of such neurohormonal activity through the use of long-acting angiotensin-converting enzyme (ACE) inhibitors, such as lisinopril, provides a means of controlling such symptoms. In comparison with short-acting ACE inhibitors, such long-acting suppression of the RAS may have a number of advantages. These include a more sustained increase in exercise duration, improvement in left ventricular ejection fraction, and, speculatively, a better influence on patient mortality.

Class effect of angiotensin-converting enzyme inhibitors on prevention of myocardial infarction.

Angiotensin-converting enzyme (ACE) inhibitors differ in their affinity for tissue-bound ACE. It has been hypothesized that tissue ACE affinity might be responsible for some of the beneficial cardiovascular properties of ACE inhibitors. The present study examined this question and found no correlation between tissue ACE affinity and risk of first nonfatal myocardial infarction in patients who have hypertension.

Effects of sulphydryl- and non-sulphydryl-containing ACE inhibitors on left ventricular relaxation in the isolated guinea pig heart.

ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (e.g remodelling, diastolic dysfunction). We have previously reported that the ACE inhibitor captopril induces selective left ventricular (LV) relaxant effects in the isolated ejecting guinea pig heart. The aim of the present study was to further investigate the mechanism of the captopril-induced changes in early LV relaxation by comparing the effects of two sulphydryl and two non-sulphydryl containing ACE inhibitors in the same experimental preparation. Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter transducer inserted in the LV cavity. The sulphydryl-containing ACE inhibitors captopril and zofenaprilat enhanced early LV relaxation, whereas the non-sulphydryl-containing ACE inhibitors lisinopril and quinaprilat did not. The effects of captopril and zofenaprilat were attenuated both by the nitric oxide-scavenger haemoglobin and the bradykinin B2-kinin receptor antagonist HOE 140. Neither the oxygen free-radical scavenger superoxide dismutase nor the sulphydryl-containing compound N-acetyl cysteine administered together with lisinopril had any effect on LV relaxation. These data demonstrate that inhibition of intra-cardiac ACE activity may acutely modulate LV relaxation through increased activity of the bradykinin-nitric oxide pathway. The presence of a sulphydryl group on the relevant ACE inhibitor appears to be essential for this LV relaxant effect.

Angiotensin-converting enzyme inhibitors. Emerging differences and new compounds.

Angiotensin-converting enzyme inhibitors (ACEIs), introduced in clinical practice in 1980, are a relatively new class of drugs. They have been useful in the treatment of hypertension, where they are effective monotherapy in 40% to 50% of the patients and in combination therapy in up to 90%. They are also useful in the symptomatic and hemodynamic improvement and in decreasing mortality of patients with congestive heart failure. In this respect, they appear to be superior to other vasodilators. The clinical success of the marketed compounds and the expected increase in market share of these drugs, estimated to approach one billion dollars in the next few years, has created great interest among clinicians and within the drug industry. The emerging differences among the three marketed ACEIs and promising new agents that are expected to be marketed in the next few years are the subject of this review.