The Pivotal Role of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertension Management and Cardiovascular and Renal Protection: A Critical Appraisal and Comparison of International Guidelines.

Arterial hypertension is the main preventable cause of premature mortality worldwide. Across Latin America, hypertension has an estimated prevalence of 25.5-52.5%, although many hypertensive patients remain untreated. Appropriate treatment, started early and continued for the remaining lifespan, significantly reduces the risk of complications and mortality. All international and most regional guidelines emphasize a central role for renin-angiotensin-aldosterone system inhibitors (RAASis) in antihypertensive treatment. The two main RAASi options are angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Although equivalent in terms of blood pressure reduction, ACEis are preferably recommended by some guidelines to manage other cardiovascular comorbidities, with ARBs considered as an alternative when ACEis are not tolerated. This review summarizes the differences between ACEis and ARBs and their place in the international guidelines. It provides a critical appraisal of the guidelines based on available evidence from randomized controlled trials (RCTs) and meta-analyses, especially considering that hypertensive patients in daily practice often have other comorbidities. The observed differences in cardiovascular and renal outcomes in RCTs may be attributed to the different mechanisms of action of ACEis and ARBs, including increased bradykinin levels, potentiated bradykinin response, and stimulated nitric oxide production with ACEis. It may therefore be appropriate to consider ACEis and ARBs as different antihypertensive drugs classes within the same RAASi group. Although guideline recommendations only differentiate between ACEis and ARBs in patients with cardiovascular comorbidities, clinical evidence suggests that ACEis provide benefits in many hypertensive patients, as well as those with other cardiovascular conditions.

Prevention of arterial and venous thrombotic events in symptomatic peripheral arterial disease patients after lower extremity revascularization in the VOYAGER PAD trial: Dual anticoagulant/antiplatelet regimen vs antiplatelet therapy alone.

BACKGROUND: Vascular disease burden after lower extremity revascularization (LER) comprises more than the first event, more vascular beds than the local arteries, and more than one clinical event type. OBJECTIVES: Assess total arterial and venous thrombotic burden after LER for symptomatic peripheral artery disease (PAD) and effect of low-dose anticoagulation added to low-dose antiplatelet therapy. PATIENTS/METHODS: VOYAGER PAD randomized 6564 symptomatic PAD patients undergoing LER to rivaroxaban 2.5 mg twice-daily or placebo on aspirin background. Marginal proportional-hazards models used to generate treatment hazard ratios and associated 95% CIs for first and total events; non-thrombotic deaths treated as competing terminal events. Incidence rates calculated as number of events per 100 patient-years follow-up. RESULTS: Over 2.5 years (median), first and total thrombotic event rates: 7.1 and 10.3 events/100 patient-years, respectively, in placebo group. Two-thirds (925/1372) of total thrombotic events (arterial 95%, venous 5%) were nonfatal first events. Nearly one-third of patients with first event had a second arterial or venous thrombotic event. Rivaroxaban plus aspirin reduced first and total arterial and venous thrombotic events to 5.4 and 7.9 events/100 patient-years, respectively, a reduction in total thrombotic events over aspirin of 23% (HR: 0.77, 95%CI: 0.67-0.89, p = .0005), preventing 6.1 total arterial and venous thrombotic events at 3 years. CONCLUSIONS: Assessing total arterial and venous thrombotic events, not just first events, provides more complete information about disease burden and absolute on-treatment impact. Following LER, judicious modulation of more than one coagulation pathway can provide broader benefit than intensifying inhibition of one hemostatic system component.

Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization: Impact of Concomitant Clopidogrel on Efficacy and Safety.

BACKGROUND: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described. METHODS: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization. RESULTS: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity (P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use (P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel (P for trend=0.06). CONCLUSIONS: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.

Prevalência e fatores de risco associados à doença arterial periférica no projeto corações do Brasil / Prevalence and risk factors associated with peripheral arterial disease in the hearts of Brazil project

FUNDAMENTO: A doença arterial obstrutiva periférica (DAOP) está associada ao maior índice de risco cardiovascular. No Brasil, faltam dados sobre sua prevalência e fatores de risco. OBJETIVO: Avaliar prevalência e fatores de risco associados à DAOP nas cidades brasileiras com > cem mil habitantes. MÉTODOS: Estudo transversal, multicêntrico, que avaliou 1.170 indivíduos (>18 anos), em 72 centros urbanos, participantes do Projeto Corações do Brasil. O diagnóstico de DAOP baseou-se na medida do índice tornozelo-braquial (ITB) < 0,90. A análise estatística utilizou teste Qui-quadrado (Pearson) corrigido para amostras complexas e intervalos de confiança. P < 0,05 foi considerado significativo. RESULTADOS: A prevalência de DAOP foi de 10,5 por cento e apenas 9 por cento dos portadores da doença apresentaram claudicação. A DAOP esteve associada à presença de diabetes, obesidade total e abdominal, acidente vascular cerebral (AVC) e doença isquêmica do coração (DIC). Houve tendência a maior prevalência de DAOP na presença de hipertensão, insuficiência cardíaca, insuficiência renal dialítica e tabagismo >20 anos/maço. Mulheres coronariopatas apresentaram risco 4,9 vezes maior de ter DAOP, do que aquelas sem coronariopatia e, entre homens diabéticos, o risco de DAOP foi 6,6 maior em comparação aos não diabéticos. CONCLUSÃO: A prevalência de DAOP foi elevada, considerando-se a baixa média de idade da população avaliada (44±14,7 anos). A minoria dos portadores apresentava claudicação, o que denota o grande contingente de indivíduos assintomáticos. Os fatores mais fortemente associados à doença foram diabetes, obesidade, AVC e DIC. Os autores concluíram que a medida do ITB deve ser considerada na avaliação de pacientes de moderado e alto risco cardiovascular.

BACKGROUND: Peripheral arterial disease (PAD) is associated with increased cardiovascular risk. In Brazil, data on PAD prevalence and risk factors are scarce. OBJECTIVE: To assess prevalence and risk factors related to PAD in Brazilian urban centers with more than 100,000 inhabitants. METHODS: National, multicenter, cross-sectional study of 1,170 individuals (>18 years), from 72 major Brazilian urban centers participating in the "Hearts of Brazil Project". PAD diagnosis was based on ankle-brachial index (ABI) < 0.90. The statistical analysis used the corrected Chi-square (Pearson) test for complex samples and confidence intervals. P< 0.05 was considered statitically significant. RESULTS: PAD prevalence was 10.5 percent. Intermittent claudication (IC) was present in only 9 percent of PAD patients. A significant association was found between PAD and the following factors: diabetes, total and abdominal obesity, stroke and ischemic heart disease (IHD). There was a trend of higher PAD prevalence among individuals with hypertension, heart failure, chronic renal failure on dialysis, as well as those who had smoked over 20 pack-years. For females, presence of IHD was associated with a 4.9-fold greater risk of PAD. Among males, a 6.6-fold increased risk of PAD was found for diabetic in comparison to non-diabetic individuals. CONCLUSION: PAD prevalence was markedly high, considering the low mean age of the studied population (44±14.7 yrs). IC was detected in a minority of PAD subjects, indicating a considerable number of asymptomatic individuals. Diabetes, obesity, stroke and IHD were the stronger predictors of PAD. The authors concluded that ABI measurement should be considered in the evaluation of moderate to high cardiovascular risk patients.

Prevalence and risk factors associated with peripheral arterial disease in the Hearts of Brazil Project.

BACKGROUND: Peripheral arterial disease (PAD) is associated with increased cardiovascular risk. In Brazil, data on PAD prevalence and risk factors are scarce. OBJECTIVE: To assess prevalence and risk factors related to PAD in Brazilian urban centers with more than 100,000 inhabitants. METHODS: National, multicenter, cross-sectional study of 1,170 individuals (>18 years), from 72 major Brazilian urban centers participating in the "Hearts of Brazil Project". PAD diagnosis was based on ankle-brachial index (ABI)

Cross-cultural adaptation and validation of the Brazilian Portuguese version of the Edinburgh Claudication Questionnaire.

OBJECTIVE: Translation, cultural adaptation and validation of the Brazilian Portuguese version of the Edinburgh Claudication Questionnaire (ECQ) a specific tool to assess intermittent claudication. METHODS: The Brazilian Portuguese version of the ECQ was developed after authorization by the University of Edinburgh. It was applied to 217 individuals: São Paulo Capital District residents with complaints of leg pain. Individuals under research were invited through mass communication media to participate in the I Campaign to Fight Peripheral Arterial Disease (PAD). In stage 1, participants filled out the ECQ and another questionnaire on risk factors and cardiovascular history. In stage 2, participants had anthropometric measures and ankle-brachial index (ABI) at rest measured by vascular Doppler. In case of doubt, vascular treadmill test was applied (VTT). PAD condition was defined by ABI < or = 0.90 and/or positive VTT and/or documented PAD. Statistical analysis--which included performance assessment and the comparison between proportions and means--was performed using SAS software, version 8.2. RESULTS: Mean age of participants was 60+/-11.5 years, female sex predominated in the sample studied (53.4%). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 85%, 93%, 80%, 95% and 91%, respectively. No differences in performance were found between elderly (> or = 65 years) and non-elderly subjects. CONCLUSION: The Brazilian Portuguese version of the Edinburgh claudication questionnaire maintained good sensitivity and specificity and can be recommended for screening of PAD in clinical practice and epidemiological research in Brazil.

Versão em português, adaptação transcultural e validação do Questionário de Claudicação de Edimburgo / Cross-cultural adaptation and validation of the Brazilian Portuguese version of the Edinburgh Claudication Questionnaire

OBJETIVO: Traduzir, adaptar culturalmente e validar a versão em português do Questionário de Claudicação de Edimburgo, específico para avaliar a presença de claudicação intermitente. MÉTODOS: A versão em português do Questionário de Claudicação de Edimburgo foi desenvolvida, após autorização da Universidade de Edimburgo, e aplicada em 217 indivíduos residentes no município de São Paulo, com queixas de dor nas pernas, convidados pelos meios de comunicação de massa a participar da I Campanha de Combate à Doença Arterial Obstrutiva Periférica (DAOP). Na primeira etapa, eles responderam ao Questionário de Claudicação de Edimburgo e a um questionário sobre fatores de risco e antecedentes cardiovasculares. Na segunda etapa, realizaram medidas antropométricas e do índice tornozelo-braquial (ITB) de repouso com Doppler vascular e, nos casos duvidosos, teste de esforço vascular em esteira (TEV). A presença de DAOP foi definida por ITB < 0,90 e/ou por TEV positivo e/ou por DAOP documentada. A análise estatística, que incluiu avaliação de desempenho e comparações das proporções e médias, foi realizada utilizando-se o programa SAS versão 8.2. RESULTADOS: A média de idade dos participantes foi de 60 ± 11,5 anos, com predomínio do sexo feminino (53,4 por cento). A análise de desempenho da versão em língua portuguesa mostrou sensibilidade de 85 por cento, especificidade de 93 por cento, valor preditivo positivo de 80 por cento, valor preditivo negativo de 95 por cento e acurácia de 91 por cento. Não houve diferença no desempenho entre idosos (> 65 anos) e não-idosos. CONCLUSÃO: A versão em português do Questionário de Claudicação de Edimburgo manteve níveis adequados de sensibilidade e especificidade, podendo ser recomendado para o rastreamento de DAOP na prática clínica e em estudos epidemiológicos realizados no Brasil.

OBJECTIVE: Translation, cultural adaptation and validation of the Brazilian Portuguese version of the Edinburgh Claudication Questionnaire (ECQ) a specific tool to assess intermittent claudication. METHODS: The Brazilian Portuguese version of the ECQ was developed after authorization by the University of Edinburgh. It was applied to 217 individuals: São Paulo Capital District residents with complaints of leg pain. Individuals under research were invited through mass communication media to participate in the I Campaign to Fight Peripheral Arterial Disease (PAD). In stage 1, participants filled out the ECQ and another questionnaire on risk factors and cardiovascular history. In stage 2, participants had anthropometric measures and ankle-brachial index (ABI) at rest measured by vascular Doppler. In case of doubt, vascular treadmill test was applied (VTT). PAD condition was defined by ABI < 0.90 and/or positive VTT and/or documented PAD. Statistical analysis - which included performance assessment and the comparison between proportions and means - was performed using SAS software, version 8.2. RESULTS: Mean age of participants was 60±11.5 years, female sex predominated in the sample studied (53.4 percent). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 85 percent, 93 percent, 80 percent, 95 percent and 91 percent, respectively. No differences in performance were found between elderly (>65 years) and non-elderly subjects. CONCLUSION: The Brazilian Portuguese version of the Edinburgh claudication questionnaire maintained good sensitivity and specificity and can be recommended for screening of PAD in clinical practice and epidemiological research in Brazil.

Effects of metoprolol and amiodarone combination on heart rate, myocardial contractility and coronary flow: Study in isolated perfused rat hearts.

BACKGROUND: Beta-blockers and amiodarone have been used concomitantly to treat arrhythmias associated with congestive heart failure. However, the combination of metoprolol and amiodarone has only been studied restrospectively, and its potential effects in congestive heart failure remain to be properly elucidated in prospective trials. OBJECTIVE: The present investigation focused on evaluating the pharmacological interaction between metoprolol and amiodarone in an isolated perfused rat heart preparation. MATERIALS AND METHODS: Adult male Wistar rats (n=24) were divided into four groups of six animals, and the effects of the metoprolol/amiodarone combination on systolic pressure, myocardial contractility (dP/dt), coronary flow (CF) and heart rate were analyzed, and the interdependent variables were compared. RESULTS: There was a negative chronotropic effect by both metoprolol and the metoprolol/amiodarone combination in isolated rat hearts. However, the acute effects of the metoprolol/amiodarone combination showed no myocardial contractility depression or bradycardia accentuation compared with metoprolol alone. CF increased by 9.2% at minute 1 through minute 5 (P=0.004) with the metoprolol/amiodarone combination. There was no difference in systolic pressure or myocardial contractility among the groups. CONCLUSIONS: The acute effects of the metoprolol/amiodarone combination in the isolated rat heart were an increase in CF, and no myocardial contractility depression or bradycardia accentuation.

Blockade of 5-HT(2A) receptors by sarpogrelate protects the heart against myocardial infarction in rats.

BACKGROUND: It has been shown that serotonin (5-hydroxytryptamine, 5-HT) is involved in exacerbating vascular abnormalities; however, its role in mediating changes in cardiac function due to myocardial injury has yet to be established. This study examined the effect of sarpogrelate, a 5-HT(2A) receptor blocker, in preventing cardiac dysfunction due to myocardial infarction (MI). METHODS AND RESULTS: Rats were treated 3 days before surgery with or without 5 mg x kg(-1) x day(-1) sarpogrelate, and the left coronary artery was ligated for 3 weeks to induce MI. Sarpogrelate reduced the mortality from 40% to 30%, infarct size from 35% to 25%, and left ventricular end diastolic pressure from 15 mm Hg to 10 mm Hg in MI rats. Electrocardiographic (ECG) tracings showed a marked deviation in the ST-segment and prolongation of the QTc interval in MI rats during the 3 weeks; these changes were attenuated by sarpogrelate pretreatment. In another set of experiments, MI rats were treated with 5 mg x kg(-1) x day(-1) sarpogrelate 1 hour after the surgery, and the hemodynamic and electrocardiograph changes were assessed at 3 weeks. This posttreatment was also found to reduce infarct size, improve cardiac function, and attenuate ECG changes. CONCLUSIONS: Sarpogrelate attenuates cardiac dysfunction, infarct size, and changes in the ECG due to MI. These results also support the view that serotonin and 5-HT(2A) may contribute to the deleterious effects of ischemic injury in the heart.