Tsushung A. Hua

Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis.

OBJECTIVES The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective. BACKGROUND Individual studies examining the effects of RAS inhibition on AF prevention have reported controversial results. METHODS All published randomized controlled trials reporting the effects of treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in the primary or secondary prevention of AF were included. RESULTS A total of 23 randomized controlled trials with 87,048 patients were analyzed. In primary prevention, 6 trials in hypertension, 2 trials in myocardial infarction, and 3 trials in heart failure were included (some being post-hoc analyses of randomized controlled trials). In secondary prevention, 8 trials after cardioversion and 4 trials assessing the medical prevention of recurrence were included. Overall, RAS inhibition reduced the odds ratio for AF by 33% (p < 0.00001), but there was substantial heterogeneity among trials. In primary prevention, RAS inhibition was effective in patients with heart failure and those with hypertension and left ventricular hypertrophy but not in post-myocardial infarction patients overall. In secondary prevention, RAS inhibition was often administered in addition to antiarrhythmic drugs, including amiodarone, further reducing the odds for AF recurrence after cardioversion by 45% (p = 0.01) and in patients on medical therapy by 63% (p < 0.00001). CONCLUSIONS This analysis supports the concept of RAS inhibition as an emerging treatment for the primary and secondary prevention of AF but acknowledges the fact that some of the primary prevention trials were post-hoc analyses. Further areas of uncertainty include potential differences among specific RAS inhibitors and possible interactions or synergistic effects with antiarrhythmic drugs.

Effect of Aliskiren on Postdischarge Mortality and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure The ASTRONAUT Randomized Trial

IMPORTANCE Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality. OBJECTIVE To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients. DESIGN, SETTING, AND PARTICIPANTS International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥ 400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥ 1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012. INTERVENTION All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months. RESULTS In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), β-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo. CONCLUSION AND RELEVANCE Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00894387.

Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: The VALUE trial

Background Atrial fibrillation (AF) is the most common arrhythmia and increases cardiovascular risk in hypertensive patients. Therefore, in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) a prespecified objective was to compare the effects of valsartan and amlodipine on new-onset AF. Methods A total of 15 245 hypertensive patients at high cardiovascular risk received valsartan 80–160 mg/day or amlodipine 5–10 mg/day combined with additional antihypertensive agents. Electrocardiograms were obtained every year and analyzed centrally for evidence of left ventricular hypertrophy and new-onset AF. Results At baseline, AF was diagnosed in 2.6% of 7649 valsartan recipients and 2.6% of 7596 amlodipine recipients. During antihypertensive treatment the incidence of at least one documented occurrence of new-onset AF was 3.67% with valsartan and 4.34% with amlodipine {unadjusted hazard ratio 0.843, [95% confidence interval (CI): 0.713, 0.997], P = 0.0455}. The incidence of persistent AF was 1.35% with valsartan and 1.97% with amlodipine [unadjusted hazard ratio 0.683 (95% CI: 0.525, 0.889), P = 0.0046]. Conclusions Valsartan-based treatment reduced the development of new-onset AF, particularly sustained AF in hypertensive patients, compared with amlodipine-based therapy. These findings suggest that angiotensin II receptor blockers may result in greater benefits than calcium antagonists in hypertensive patients at risk of new-onset AF.

Cardiovascular Events During Differing Hypertension Therapies in Patients With Diabetes

OBJECTIVES The aim of this study was to determine which combination therapy in patients with hypertension and diabetes most effectively decreases cardiovascular events. BACKGROUND The ACCOMPLISH (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension) trial compared the outcomes effects of a renin-angiotensin system blocker, benazepril, combined with amlodipine (B+A) or hydrochlorothiazide (B+H). A separate analysis in diabetic patients was pre-specified. METHODS A total of 6,946 patients with diabetes were randomized to treatment with B+A or B+H. A subgroup of 2,842 diabetic patients at very high risk (previous cardiovascular or stroke events) was also analyzed, as were 4,559 patients without diabetes. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for angina, resuscitated arrest, and coronary revascularization. RESULTS In the full diabetes group, the mean achieved blood pressures in the B+A and B+H groups were 131.5/72.6 and 132.7/73.7 mm Hg; during 30 months, there were 307 (8.8%) and 383 (11.0%) primary events (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.68 to 0.92, p = 0.003). For the diabetic patients at very high risk, there were 195 (13.6%) and 244 (17.3%) primary events (HR: 0.77, 95% CI: 0.64 to 0.93, p = 0.007). In the nondiabetic patients, there were 245 (10.8%) and 296 (12.9%) primary events (HR: 0.82, 95% CI: 0.69 to 0.97, p = 0.020). In the diabetic patients, there were clear coronary benefits with B+A, including both acute clinical events (p = 0.013) and revascularizations (p = 0.024). There were no unexpected adverse events. CONCLUSIONS In patients with diabetes and hypertension, combining a renin-angiotensin system blocker with amlodipine, compared with hydrochlorothiazide, was superior in reducing cardiovascular events and could influence future management of hypertension in patients with diabetes. (Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension [ACCOMPLISH]; NCT00170950).

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial: Outcomes in Patients Receiving Monotherapy

In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE trial. In the first analysis, we censored patients when they discontinued monotherapy (“censored”); in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios: 0.63, P=0.004 and 0.78, P=0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios: 0.78, P=0.012 and 0.82, P=0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.

Impact of New-Onset Diabetes Mellitus on Cardiac Outcomes in the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial Population

There has been a lot of interest about new-onset diabetes mellitus in recent hypertension trials, but the implications of diabetes development on cardiac outcomes have not been known. In the Valsartan Antihypertensive Long-Term Use Evaluation trial, 15 245 high-risk patients were followed for an average of 4.2 years. At baseline, 5250 patients were diabetic by the 1999 World Health Organization criteria, and among the 9995 nondiabetic patients, 1298 patients developed diabetes during follow-up. We have investigated the influence of diabetes development on outcomes in the Valsartan Antihypertensive Long-Term Use Evaluation trial. The patients with diabetes at baseline and new-onset diabetes were compared with patients who did not develop diabetes by a Cox regression model with adjustment for prespecified covariates (age, diabetes status, left ventricular hypertrophy, baseline coronary heart disease, and randomized study treatment). Patients with diabetes at baseline had the highest cardiac morbidity defined as myocardial infarction and heart failure with a hazard ratio of 2.20 (95% CI: 1.95 to 2.49). The patients with new-onset diabetes had significantly higher cardiac morbidity, especially more congestive heart failure, than those without diabetes, with a hazard ratio of 1.43 (95% CI: 1.16 to 1.77). This indicates that patients who develop diabetes during antihypertensive treatment have cardiac morbidity intermediate between diabetic subjects and those subjects who never had diabetes and that it is of importance to find these patients at risk of diabetes development and optimize lifestyle and medical treatment.

Prediction of cardiovascular outcome by estimated glomerular filtration rate and estimated creatinine clearance in the high-risk hypertension population of the VALUE trial.

Background Reduced renal function is predictive of poor cardiovascular outcomes but the predictive value of different measures of renal function is uncertain. Methods 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 ≥ 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. Results 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. Conclusion 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.

Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p <0.05). The adjusted hazard ratio for the primary end point in the highest in-trial HR heart rate quintile versus the lowest quintile was 1.53 (95% confidence interval 1.26 to 1.85). The incidence of primary end points in the highest in-trial HR group compared to the pooled 4 lower quintiles was 53% greater in patients with well-controlled blood pressure (p <0.001) and 34% greater in those with uncontrolled blood pressure (p = 0.002). In conclusion, an increased HR is a long-term predictor of cardiovascular events in patients with high-risk hypertension. This effect was not modified by good blood pressure control. It is not yet known whether a therapeutic reduction of HR would improve cardiovascular prognosis.

Diuretic response in patients with acute decompensated heart failure: Characteristics and clinical outcome - An analysis from RELAX-AHF

We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).

Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial

AIMS Recent hypertension guidelines recommend that also in high cardiovascular (CV) risk, hypertensive patients blood pressure (BP) is lowered to <140/90 mmHg as no evidence is available supporting the lower target of <130/80 mmHg recommended in previous guidelines. Whether this represents the optimal treatment strategy is debated, however. METHODS AND RESULTS The high CV risk hypertensive patients of the Valsartan Antihypertensive Long-term use Evaluation (VALUE) trial were divided into subgroups according to (i) the percentage of on-treatment visits in which BP was reduced to <140/90 or <130/80 mmHg or (ii) the mean systolic or diastolic BP (SBP/DBP) values achieved during the entire treatment period or up to the occurrence of an event. A progressive increase from <25 to ≥75% of the visits in which BP was <140/90 mmHg was accompanied by a significant, progressive marked decrease in the covariate adjusted risk of CV morbidity and mortality, cause specific CV events (myocardial infarction, heart failure, and stroke), and all-cause mortality. Except for a persistent progressive decrease in stroke, no significant trend to a risk decrease occurred for a similar progressive increment of the proportion of visits with BP <130/80 mmHg. Increasing the proportion of visits with a BP <140/90 mmHg (but not <130/80 mmHg) was accompanied by a decreased risk of events also when differences in baseline risk were adjusted using a propensity score. Finally, compared with patients remaining at a mean on-treatment SBP ≥140 or DBP ≥90 mmHg, the risk of all events was markedly reduced when on-treatment mean SBP was lowered to a mean SBP of 130-139 mmHg or a mean DBP of 80-89 mmHg, whereas at on-treatment mean SBP <130 mmHg or DBP <80 mmHg, an additional risk reduction was found for stroke but for any other type of event, the risk of which remained similar or only slightly greater than that seen at the higher BP target. CONCLUSIONS In the high CV risk, hypertensives of the VALUE trial reducing BP consistently to <140/90 mmHg had marked beneficial effects both when data were calculated as proportion of visits at BP target or as on-treatment mean BP. Reducing BP to <130/80 mmHg led only to some possible further benefit on stroke, whereas the risk of other outcomes remained substantially similar to or slightly greater than that seen at the higher target. Thus, aggressive BP reductions when CV risk is high may not offer substantial advantages, except perhaps in patients or conditions in which stroke risk is particularly common.