Amlodipine

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

Systemic arterial hypertension affects 72 million US adults and an additional hundreds of millions of persons worldwide.1,2 Most of these are candidates for pharmacological treatment to reduce risk of cardiovascular disease (CVD) events, based primarily on a very large body of epidemiological and intervention research in humans. Because of this high prevalence and the cardiovascular consequences of untreated or inadequately treated hypertension, the selection of drugs for initial and continuing, long-term treatment has large public health and economic implications. Fortunately, such decisions and the expert recommendations that seek to guide them can call on evidence from 4 decades of randomized multicenter clinical trials evaluating effects of treatment on clinical CVD. We summarize that evidence in this article, in approximate chronological order, and we comment on the related treatment guidelines. We close with some of the major clinical questions yet to be resolved. Response by Messerli et al p 2705 Before the current era beginning in the early 1990s of emphasis on positive-control trials, which directly compare different drug regimens, there were 3 decades of trials that compared an active regimen with placebo or, in a few cases, “usual care.” For most of this period, the mainstay of treatment was generally a thiazide-type diuretic (hereinafter called thiazides) or, to a lesser extent, a β-adrenergic blocker (termed β-blockers). With few exceptions, these trials, especially those with high statistical power and thiazide-based regimens, showed benefit for CVD outcomes.3–8 This evidence, which provided a basis for recommending thiazides or β-blockers as first-step drugs in most editions of US guidelines through 1997,9 needs to continue to be given due weight in practice and practice guidelines. The largest and most consistent benefits from the earlier trials were for stroke and (where reported) heart failure. Benefits for coronary heart disease (CHD) were less clear, …

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) compared in >30 000 high-risk hypertensive patients the effects on coronary heart disease of 3 treatment strategies: (1) based on the diuretic chlorthalidone, (2) the calcium-channel blocker (CCB) amlodipine, and (3) the angiotensin converting-enzyme (ACE) inhibitor lisinopril, respectively.1 Sponsored by the National Heart, Lung, and Blood Institute, ALLHAT stands out because no differences occurred in the incidence of the primary end point that consisted of the combination of fatal coronary heart disease and acute myocardial infarction.1 Not surprisingly, the attention of the ALLHAT consortium shifted to secondary end points, such as stroke, or to loosely defined2 components of secondary end points, such as heart failure. At the end of the line, the ALLHAT investigators based their main conclusions on events that, at the initiation of the trial, they regarded as “soft data that will at best confirm or supplement the primary endpoint.”3 More importantly, what was not identical in the 3 treatment groups was the on-treatment blood pressure despite vigorous attempts to titrate and combine the study medications to achieve a blood pressure of <140 mm Hg systolic and 90 mm Hg diastolic.1 These salient features of ALLHAT should be kept in mind whenever one attempts to interpret the findings of this landmark trial. In this issue of Hypertension , Leenen et al4 published a post hoc analysis, in which they made a direct comparison of cardiovascular and other outcomes among the 18 102 ALLHAT participants randomly assigned to amlodipine or lisinopril. In line with previous reports,1 the incidence of the primary coronary end point and total and cardiovascular mortality were similar in both groups. However, the patients randomly assigned to lisinopril experienced higher risks of stroke, combined cardiovascular disease, gastrointestinal bleeding, …

Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial

The safety of angiotensin II receptor blockers (ARBs) for the treatment of hypertension and cardiovascular and renal diseases has been well documented in numerous randomized clinical trials involving thousands of patients. However, recent concerns have surfaced about possible links between ARBs and increased risks of myocardial infarction and cancer. Less is known about the safety of the direct renin inhibitor aliskiren, which was approved as an antihypertensive in 2007. This article provides a detailed review of the safety of ARBs and aliskiren, with an emphasis on the risks of cancer and myocardial infarction associated with ARBs. Safety data were identified by searching PubMed and Food and Drug Administration (FDA) Web sites through April 2011. ARBs are generally well tolerated, with no known class-specific adverse events. The possibility of an increased risk of myocardial infarction associated with ARBs was suggested predominantly because the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial reported a statistically significant increase in the incidence of myocardial infarction with valsartan compared with amlodipine. However, no large-scale, randomized clinical trials published after the VALUE study have shown a statistically significant increase in the incidence of myocardial infarction associated with ARBs compared with placebo or non-ARBs. Meta-analyses examining the risk of cancer associated with ARBs have produced conflicting results, most likely due to the inherent limitations of analyzing heterogeneous data and a lack of published cancer data. An ongoing safety investigation by the FDA has not concluded that ARBs increase the risk of cancer. Pooled safety results from clinical trials indicate that aliskiren is well tolerated, with a safety profile similar to that of placebo. ARBs and aliskiren are well tolerated in patients with hypertension and certain cardiovascular and renal conditions; their benefits outweigh possible safety concerns.

The Valsartan Amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However, we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group. There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.

Hypertension is a widely diffused clinical condition in the general population and it is often associated with people who are overweight (i.e. have abdominal adiposity) or obese and with metabolic syndrome. Evidence shows that hypertensive patients are at increased risk of developing type 2 diabetes mellitus (T2DM) since angiotensin II is involved in the pathogenesis of hypertension and insulin resistance, which are both the key components of metabolic syndrome. The preventive effect of renin-angiotensin system (RAS) inhibition on the development of T2DM could reflect the closely linked mechanisms of blood pressure and blood glucose homeostasis. Since hyperglycaemia is a consequence of insulin resistance and β-cell dysfunction, preventing T2DM by RAS inhibition may result from an improvement of β-cell function and/or an enhancement of insulin sensitivity, which are secondary to modifications in microcirculation and changes in ionic status. On the basis of this hypothesis, several trials in treating hypertensive patients have shown a positive effect of drugs inhibiting RAS in reducing the number of hypertensive patients that develop T2DM. We analysed the results of the following clinical studies that found a reduction in the incidence of new-onset T2DM in hypertensive patients using angiotensin II type 1 receptor blockers (ARBs): LIFE (Losartan Intervention For Endpoint reduction in hypertension) [losartan]; SCOPE (Study on COgnition and Prognosis in the Elderly) [candesartan]; ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation) [candesartan]; CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) [candesartan]; and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) [valsartan]. We analysed the results of the following clinical studies that found a reduction in the incidence of new-onset T2DM in hypertensive patients using angiotensin II type 1 receptor blockers (ARBs): LIFE (Losartan Intervention For Endpoint reduction in hypertension) [losartan]; SCOPE (Study on COgnition and Prognosis in the Elderly) [candesartan]; ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation) [candesartan]; CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) [candesartan]; and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) [valsartan]. Evidence shows that blood pressure reduction, when associated with lifestyle modifications (especially in high-risk patients), is more important than the mechanism of action of the antihypertensive drugs, which is to normalise blood pressure and thus reduce the incidence of cardiovascular events. In this regard, the identification of the potential influence of RAS inhibition in preventing new-onset T2DM in hypertensive subjects is a promising topic for the healthcare system. In the future, data from the ongoing trials, where prevention of diabetes is the primary endpoint, may prove to what extent this class of drugs is actually effective. However, in the previously mentioned clinical trials, the superior effectiveness of ARBs in preventing T2DM is associated with a lower efficacy in preventing cardiovascular events, because of their lesser capacity in lowering blood pressure. Evidence so far suggests the use of ARBs preferably in association with other classes of antihypertensive drugs and under a constant control of blood pressure. In this latter regard, in the recently published ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm) study, a combination therapy based on a drug inhibiting RAS (perindopril) and a calcium-channel blocker (amlodipine) significantly reduced the incidence of major cardiovascular events and new onset of diabetes in high-risk hypertensive patients, compared with a combination therapy based on thiazide diuretic and a β-blocker.

Reduced renal function is predictive of poor cardiovascular outcomes but the predictive value of different measures of renal function is uncertain. We compared the value of estimated creatinine clearance, using the Cockcroft-Gault formula, with that of estimated glomerular filtration rate (GFR), using the Modification of Diet in Renal Disease (MDRD) formula, as predictors of cardiovascular outcome in 15 245 high-risk hypertensive participants in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. For the primary end-point, the three secondary end-points and for all-cause death, outcomes were compared for individuals with baseline estimated creatinine clearance and estimated GFR < 60 ml/min and > or = 60 ml/min using hazard ratios and 95% confidence intervals. Coronary heart disease, left ventricular hypertrophy, age, sex and treatment effects were included as covariates in the model. For each end-point considered, the risk in individuals with poor renal function at baseline was greater than in those with better renal function. Estimated creatinine clearance (Cockcroft-Gault) was significantly predictive only of all-cause death [hazard ratio = 1.223, 95% confidence interval (CI) = 1.076-1.390; P = 0.0021] whereas estimated GFR was predictive of all outcomes except stroke. Hazard ratios (95% CIs) for estimated GFR were: primary cardiac end-point, 1.497 (1.332-1.682), P < 0.0001; myocardial infarction, 1.501 (1.254-1.796), P < 0.0001; congestive heart failure, 1.699 (1.435-2.013), P < 0.0001; stroke, 1.152 (0.952-1.394) P = 0.1452; and all-cause death, 1.231 (1.098-1.380), P = 0.0004. These results indicate that estimated glomerular filtration rate calculated with the MDRD formula is more informative than estimated creatinine clearance (Cockcroft-Gault) in the prediction of cardiovascular outcomes.

The ambulatory blood pressure (ABP) monitoring substudy of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was carried out in a subset of patients from USA, Italy and Denmark. ABP was measured after 1 year in the trial, with the aim of evaluating comparability of ABP levels on valsartan (VAL) and amlodipine (AML)-based regimens. ABP was measured every 20 min during a 25-h period after morning administration of medicine; 659 patients were available for intention-to-treat analysis. Office blood pressure (BP) differences were smaller than in the main study and mean ABP levels also showed only minor differences between the two regimens (VAL, 132.5/74.8 mmHg; AML, 131.5/75.2 mmHg). However, during the first 7 h after dosing, ABP was lower on VAL, whereas AML exerted a significantly stronger effect during the last 4 h of the dosing interval--possibly influencing the differences in office BP found in the main study. Mean heart rate (HR) was higher on AML (72.3 bpm) than on VAL (70.5 bpm) (P = 0.013), suggesting a sustained difference in sympathetic activation. Correlation analysis showed a close relationship between treated ABP levels and the occurrence of combined cardiovascular endpoints--superior to the relationship to office BP. In these elderly high-risk patients, diastolic ABP levels tended to be less predictive than systolic, and daytime less predictive than night-time for all cardiovascular endpoints. The findings underline the importance of ABP substudies in comparative trials for elucidating significant differences in pharmacodynamics, and stresses the superior predictive power of ABP.

Advantages of new cardiovascular risk-assessment strategies in high-risk patients with hypertension

Usefulness of Heart Rate to Predict Cardiac Events in Treated Patients With High-Risk Systemic Hypertension

Background:Heart failure is a chronic condition that imposes a significant burden on healthcare systems worldwide. Effective management is crucial for improving patient outcomes and reducing costs. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are widely used to manage heart failure by reducing cardiac strain and preventing disease progression. Despite their common use, ACE inhibitors and ARBs differ in mechanisms, cost, and potential side effects. ACE inhibitors have long been the standard treatment, while ARBs are often prescribed to patients intolerant to ACE inhibitors, particularly due to side effects like cough. Given these differences, evaluating the cost-effectiveness of these treatments is essential. This study compares the cost-effectiveness of ACE inhibitors and ARBs from a healthcare system perspective, considering both direct medical costs and health outcomes.Methods:A cost-effectiveness analysis was conducted using a decision-analytic Markov model to simulate heart failure progression in a hypothetical cohort. Data inputs included clinical trial outcomes, real-world effectiveness data, direct medical costs (medications, hospitalizations, monitoring), and utility values for quality of life. The primary outcome measures were the cost per quality-adjusted life year gained and the incremental cost-effectiveness ratio. Sensitivity analyses tested the robustness of results, and subgroup analyses were conducted based on age and disease severity.Results:The base-case analysis showed that ACE inhibitors were associated with lower overall costs and slightly higher quality-adjusted life years than ARBs. Sensitivity analyses revealed that variations in key parameters, such as transition probabilities, mortality rates, and healthcare expenses, had limited impact on the overall cost-effectiveness conclusions. Subgroup analyses indicated that ACE inhibitors and ARBs exhibited similar cost-effectiveness profiles for patients aged <65 and ≥65 years. However, among patients with severe heart failure, ARBs demonstrated a higher incremental cost-effectiveness ratio compared with ACE inhibitors, suggesting reduced cost-effectiveness in this subgroup.Conclusion:ACE inhibitors are likely a more cost-effective option for managing heart failure than ARBs, particularly from a healthcare system perspective. The findings underscore the importance of tailoring treatment decisions to individual patient factors, preferences, and clinical conditions, providing valuable insights for healthcare policy and practice, particularly regarding cost-effectiveness across patient subgroups.

Therapeutic Controversies in Hypertension

Comparison of a calcium antagonist and an ACE inhibitor in the treatment of elderly hypertensive patients