Valsartan In Acute Myocardial Infarction Research Articles

Uncertainty on the Use of Aldosterone Antagonists for Primary Therapy for Sudden Cardiac Death in the Setting of Implanted Devices

In the early development of therapy for acute myocardial infarction, it was thought that once the necrotic process had been completed (usually within 24 hours of coronary artery occlusion), additional therapies could not affect outcome. However, after completion of the necrotic process, the myocardial infarction may thin and stretch (involving lengthwise slippage of myocytes), a phenomenon referred to as myocardial infarct expansion. This process causes local left ventricular cavity dilatation followed by gradual global left ventricular dilatation and lengthwise (eccentric) hypertrophy of the noninfarcted tissue. Apoptosis (programmed cell death) and some attempt of the myocardium to regenerate, especially at the infarct border zone, may also contribute to this remodeling process of the ventricle. If the left ventricle remodels in such a way that it becomes very dilated, then the prognosis is poor, and heart failure is more likely to occur.1 These later processes of myocardial infarct expansion and left ventricular remodeling became the target of therapies such as angiotensin-converting enzyme (ACE) inhibition that could be initiated after 24 hours of coronary occlusion. ACE inhibition, angiotensin receptor blockade, and long-term β-blockade have become standard pharmacological approaches for postinfarction left ventricular dysfunction and heart failure. Response by Pitt and Pitt p 2989 Ventricular arrhythmias can occur in both the acute and chronic phases of acute myocardial infarction and can lead to sudden cardiac death (SCD). Reentrant arrhythmias may arise at the border zone of infarcts, causing monomorphic ventricular tachycardia that may occur years after the index infarction. Recurrent myocardial ischemia resulting in an unstable substrate may contribute to polymorphic ventricular tachycardia or ventricular fibrillation. Agents such as β-blockers that are anti-ischemic may reduce sudden death by quieting this unstable substrate. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable defibrillators were shown to reduce mortality in post–myocardial infarction patients with …

Long-term outcomes of left bundle branch block in high-risk survivors of acute myocardial infarction: The VALIANT experience

In survivors of myocardial infarction (MI), new left bundle branch block (LBBB) is associated with adverse outcomes, but its impact is not well described in post-MI patients with left ventricular (LV) systolic dysfunction and/or heart failure (HF). The aim of this study was to determine if new LBBB is an independent predictor of long-term fatal and nonfatal outcomes in high-risk survivors of MI by reviewing data from the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. In VALIANT, 14,703 patients with LV systolic dysfunction and/or HF were randomized to valsartan, captopril, or both a mean of 5 days after MI. Baseline ECG data were available from 14,259 patients. We assessed the predictive value of new LBBB for death and major cardiovascular outcomes after 3 years, adjusting for multiple baseline covariates including LV ejection fraction. At follow-up, patients with new LBBB (608 [4.2%]) compared with patients without new LBBB had more comorbidities and increased adjusted risk of death (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.2-1.6), cardiovascular death (HR 1.4, 95% CI 1.2-1.7), HF (HR 1.3, 95% CI 1.1-1.6), MI (HR 1.5, 95% CI 1.2-1.9), and the composite of death, HF, or MI (HR 1.4, 95% CI 1.2-1.6). In post-MI survivors with LV systolic dysfunction and/or HF, new LBBB was an independent predictor of all major adverse cardiovascular outcomes during long-term follow-up. This readily available ECG marker should be considered a major risk factor for long-term cardiovascular complications in high-risk patients after MI.

Geographic variation in the treatment of acute myocardial infarction in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial

The VALIANT trial compared the efficacy and safety of captopril, valsartan, and their combination in patients with left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction (MI). By examining this international trial population of high-risk patients, we sought to determine geographic variations in the use of 3 key treatments for MI. We analyzed data from 14,512 high-risk patients with MI in the VALIANT trial from the 20 countries that had enrolled >100 patients. International variation in the proportion of patients receiving (1) reperfusion therapy (thrombolysis or primary percutaneous coronary intervention), (2) beta-blockers, or (3) aspirin at the time of MI was measured by using adjusted W scores. These scores correspond to the number of additional or fewer patients who received each of the therapies compared with the number expected, as estimated from multivariable regression models that account for patients' baseline characteristics. There was marked variation between countries in the use of reperfusion therapy (equivalent to a difference of up to 36/100 potentially eligible patients) and beta-blockers (41/100), whereas there was much less variation in the use of aspirin (13/100). Marked geographic variation persists in the use of standard evidence-based therapy advocated by international guidelines. Our findings have implications not only for care of patients but also for the conduct of international trials.

Association of QRS duration and outcomes after myocardial infarction: the VALIANT trial

Prolongation of the QRS duration has been shown to be associated with adverse outcomes among heart failure (HF) patients. The association of QRS duration with clinical outcomes in the post-myocardial infarction (MI) setting is less well defined. To assess the prognostic significance of QRS duration prolongation on initial electrocardiogram after acute MI. QRS duration was measured in 403 patients with MI complicated by left ventricular dysfunction, signs or symptoms of HF, or both, who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echo study. The cohort was divided into quartiles of QRS duration (<75 ms, 75-88 ms, 89-108 ms, >108 ms). The number of clinical events were determined and compared across the groups. Increasing QRS duration is associated with a higher incidence of HF, sudden death (SD), and cardiovascular (CV) death (P-trend <0.05) but not with stroke or recurrent MI. The univariate relative risks for HF, SD, and CV death with increasing QRS duration quartiles were 1.31 (95% CI, 1.06-1.64), 1.57 (95% CI, 1.03-2.40), and 1.31 (95% CI, 1.03-1.66), respectively, but QRS duration did not remain independently predictive of adverse outcome after adjusting for the 10 most predictive baseline covariates. Baseline end-diastolic and end-systolic volumes were larger and ejection fraction was lower in the higher QRS quartile groups. Prolonged QRS duration, even within the normal range, is associated with larger ventricular volumes, reduced systolic function, and an increased risk for development of HF, SD, and CV death after MI but appears to be a marker, rather than an independent predictor, for increased risk.

Left Ventricular Assessment in Myocardial Infarction

How often echocardiography and cardiac catheterization are used to evaluate left ventricular (LV) function in patients with myocardial infarction (MI) and how they are associated with quality of care is unknown. Patients with MI in the Valsartan in Acute Myocardial Infarction (VALIANT) registry were divided into those with (n = 1423) and without (n = 3968) heart failure (HF), and the use of either echocardiography or cardiac catheterization for LV assessment in each group was compared along with associated baseline characteristics. We evaluated the association between LV assessment and discharge medications. Using a multivariable model with a propensity analysis, we evaluated the association of LV assessment with in-hospital outcomes. Of the patients with HF, 322 (22.6%) had no LV assessment. Patients with HF with LV assessment were discharged more frequently under treatment with aspirin (81.3% vs 70.0%; P<.001), beta-blockers (65.6% vs 56.4%; P = .008), clopidogrel (30.4% vs 14.0%; P<.001), and statins (45.9% vs 34.2%; P<.001). Patients without HF who underwent LV assessment were discharged more frequently under treatment with an angiotensin-converting enzyme inhibitor (53.8% vs 41.5%; P<.001). After adjustment for regional use, other covariates, and revascularization, LV assessment was associated with lower in-hospital mortality in patients with HF (adjusted odds ratio [OR], 0.45; P<.001) and in patients without HF (adjusted OR, 0.30; P<.001). After excluding deaths during the first 2 days, LV assessment remained associated with lower mortality in patients with HF (adjusted OR, 0.59; P = .03) and in patients without HF (adjusted OR, 0.41; P<.001). Left ventricular assessment was frequently not performed during the in-hospital stay of patients with acute MI, including those with clinical HF, and its use was associated with better quality of care.

The role of angiotensin II receptor blockers in the management of heart failure

Angiotensin-converting enzyme inhibitors (ACE-inhibitors) are first-line treatment for chronic heart failure (CHF) with a low left ventricular ejection fraction because they improve symptoms and reduce mortality and admission to hospital. Many CHF patients do not receive these agents because of intolerance. Like ACE-inhibitors, angiotensin II type 1 receptor blockers (ARBs) reduce the action of angiotensin II but achieve this effect by an alternative mechanism, thus they may be effective in patients who are intolerant to ACE-inhibitors. Recommendations concerning the efficacy of ARBs in CHF, in the 2001 European Society of Cardiology (ESC) guidelines, were appropriately cautious and their use has remained limited, reflecting uncertainties concerning their role in CHF. However, a number of large-scale clinical trials (including OPtimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan, VALsartan In Acute Myocardial iNfarcTion, and Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) have been completed since the publication of the 2001 guidelines that support the efficacy and safety of ARBs in CHF. Findings from these trials suggest that ARBs may improve outcomes across the CHF patient spectrum, including those with preserved or low ejection fractions, ACE-intolerant patients, in all cases as part of a polytherapeutic strategy. On the basis of these trial data, the revised 2005 ESC guidelines provide stronger recommendations for the use of ARBs in the management of CHF.

Heart failure on admission and the risk of stroke following acute myocardial infarction: the VALIANT registry

We sought to assess the relative contribution of heart failure (HF) on admission for an acute myocardial infarction (MI) to the subsequent in-hospital stroke risk. The VALsartan In Acute myocardial iNfarcTion (VALIANT) registry enrolled 5573 consecutive MI patients at 84 international sites from 1999 to 2001. We calculated odds ratios (ORs) for stroke and adjusted for baseline characteristics, Killip Class, and risk factors for stroke, such as diabetes and prior HF. In-hospital stroke occurred in 81 (1.5%) patients. HF was present on admission in 38% of patients who developed a stroke and in 24% who did not (P=0.001). Older age (OR 1.03 increase/year, 95% confidence interval (CI) 1.01-1.04), Killip Class III (OR 1.66, CI 0.86-3.19) or IV (OR 4.85, CI 1.69-13.93), history of hypertension (OR 1.73, CI 1.06-2.82), and history of stroke (OR 1.89, CI 1.06-3.37) were more common in patients who had in-hospital stroke. In-hospital mortality in patients with and without stroke was 27.2 and 6.5%, respectively (P<0.001). Patients with stroke after MI have a dismal prognosis. The presence of HF on admission for an acute MI increases in-hospital stroke risk. HF treatments may modify the risk of stroke.

Changes in Ventricular Size and Function in Patients Treated With Valsartan, Captopril, or Both After Myocardial Infarction

Angiotensin-converting enzyme (ACE) inhibitors have been shown to attenuate left ventricular (LV) enlargement in association with reducing mortality after myocardial infarction (MI). Preclinical data suggest that angiotensin receptor blockers (ARBs) may have similar structural and functional effects after MI. The Valsartan in Acute Myocardial Infarction (VALIANT) Echo study was designed to test the hypothesis that the ARB valsartan, either alone or in combination with captopril, could attenuate progressive LV enlargement or improve LV ejection fraction to a greater extent than captopril alone. Six hundred ten patients enrolled in the main VALIANT study who experienced MI and evidence of LV dysfunction, heart failure, or both were enrolled in the VALIANT Echo study. Patients were randomized to receive valsartan 160 mg PO BID, captopril 50 mg PO TID, or valsartan 80 mg PO BID plus captopril 50 mg PO TID between 1 and 10 days after MI. Six hundred three patients had echocardiograms of sufficient quality for quantitative analysis. Echocardiograms were digitized, and endocardial borders were traced manually from 2 short-axis and 2 apical views. Ventricular volumes, ejection fractions, combined areas, and infarct segment length were measured, and changes in echocardiographic measures from baseline to 20 months were compared between treatment groups. Baseline clinical and echocardiographic characteristics were similar in the 3 treatment arms. The changes from baseline to 20 months in all echocardiographic parameters were similar in all 3 treatment arms. Baseline echocardiographic measures of ejection fraction, end-diastolic volume, and infarct segment length were highly predictive of outcomes including total mortality, death or hospitalization for heart failure, or death or any cardiovascular event (heart failure, MI, stroke, resuscitated sudden death), even after adjustment for known covariates. Treatment with the ACE inhibitor captopril, valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction, and infarct segment length between baseline and 20 months after MI. Baseline echocardiographic measures were powerfully and independently predictive of all major outcomes.

VALIANT (VALsartan In Acute myocardial iNfarcTion) trial

Angiotensin-converting enzyme inhibitors (ACE-Is) are an evidence-based treatment for patients who after myocardial infarction (MI) present with either heart failure (HF) or left ventricular systolic dysfunction, or both. An alternative could be a more complete inhibition of the renin–angiotensin system through the blockade of the angiotensin type 1 receptors. The effect of valsartan or captopril, or the combination of the two in post-MI HF or systolic dysfunction or both, has been evaluated in the VALIANT (VALsartan In Acute myocardial iNfarcTion) trial. Total mortality and the combined secondary end point of cardiovascular death, MI or HF were not significantly different in the three groups after 24.7months of follow-up. Valsartan was not inferior to captopril in terms of total mortality and cardiovascular death, MI and HF. Valsartan can be considered an alternative treatment to ACE-I in these patients.

Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: The VALsartan in Acute myocardial iNfarcTion (VALIANT) trial

Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: The VALsartan in Acute myocardial iNfarcTion (VALIANT) trial

Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.

A prior diagnosis of diabetes mellitus is associated with adverse outcomes after acute myocardial infarction (MI), but the risk associated with a new diagnosis of diabetes in this setting has not been well defined. We assessed the risk of death and major cardiovascular events associated with previously known and newly diagnosed diabetes by studying 14,703 patients with acute MI enrolled in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Patients were grouped by diabetic status: previously known diabetes (insulin use or diagnosis of diabetes before MI, n=3400, 23%); newly diagnosed diabetes (use of diabetic therapy or diabetes diagnosed at randomization [median 4.9 d after infarction], but no known diabetes at presentation, n=580, 4%); or no diabetes (n=10,719). Patients with newly diagnosed diabetes were younger and had fewer comorbid conditions than did patients with previously known diabetes. At 1 year after enrollment, patients with previously known and newly diagnosed diabetes had similarly increased adjusted risks of mortality (hazard ratio [HR] 1.43; 95% confidence interval [CI], 1.29 to 1.59 and HR, 1.50; 95% CI, 1.21 to 1.85, respectively) and cardiovascular events (HR, 1.37; 95% CI, 1.27 to 1.48 and HR, 1.34; 95% CI, 1.14 to 1.56). Diabetes mellitus, whether newly diagnosed or previously known, is associated with poorer long-term outcomes after MI in high-risk patients. The poor prognosis of patients with newly diagnosed diabetes, despite having baseline characteristics similar to those of patients without diabetes, supports the idea that metabolic abnormalities contribute to their adverse outcomes.

Does the Gender Gap Still Persist after Myocardial Infarction? Treatments and Outcomes in VALIANT

Purpose: Previously women were shown to receive inferior treatment and have worse outcomes than men after acute myocardial infarction (MI). We examined whether this “gender gap” persists in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Methods: VALIANT enrolled 14,703 patients (31% women) with left ventricular systolic dysfunction (LVSD), heart failure (HF), or both 12 hours to 10 days post-MI (median 4.9 days). The independent effect of gender on all-cause death, cardiovascular (CV) death, or hospitalization for HF and a broader composite CV endpoint (CV death, MI, hospitalization for HF, stroke, or resuscitated sudden death) over the 3 years after randomization was examined using multivariable (MV) modelling. Results: Women were older than men (69.3 yrs vs 62.8 yrs; P<0.0001), had more co-morbidity, and less often received standard drug therapy or coronary procedures (Table). Three-year mortality rates were: women 23.2%, men 17.8%. Substantially more women developed HF. CV death or HF hospitalization was: women 34%, men 24%; in the MV model, gender was an independent predictor of this outcome (HR 1.13; 95% CI 1.04–1.22) but not of overall death. Composite CV endpoint rates were: women 38.7%, men 30.1% (HR 1.12; 1.04–1.20). Conclusions: Significant differences in the treatment of men and women persist after MI. The risk for HF remains higher in women and the effect of gender on CV morbidity requires further investigation.

Who is at risk of early Hypotension and renal dysfunction with an inhibitor of the Renin Angiotensin System after myocardial infarction? data from VALIANT

Purpose: Renin angiotensin system (RAS) inhibitors are recommended in patients with myocardial infarction (MI) complicated by left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). However, their use can be followed by hypotension (HYPO) and/or renal dysfunction (RD) which are known to have a negative impact on patient outcome. The aim of this analysis was to identify the independent predictors of early HYPO or RD in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial in which all enrolled patients received a RAS inhibitor. Methods: VALIANT enrolled 14,703 patients with HF, LVSD, or both 0.5 to 10 days after MI (median 4.9 days). Patients were randomized to receive valsartan (V), captopril (C), or combination (V+C). For the purpose of this analysis, we considered only the HYPO/RD events occurring within 30 days from the beginning of study treatment and leading to study drug discontinuation. Uni- and multivariable analyses were performed to identify the independent predictors of HYPO/RD. Results: HYPO occurred in 107/14206 (0.8%) patients (C 0.5%, V 0.7%, V+C 1.1%), while RD in 61/14206 (0.4%) (C 0.4%, V 0.3%, V+C 0.7%). See Table 1 for variables. Conclusions: The occurrence of HYPO/RD leading to study drug discontinuation within 30 days from randomization in the VALIANT study was low. Combination treatment (C+V) was independently associated with a higher rate of occurrence of these events. Age, low systolic blood pressure (SBP) and treatment with potassium sparing diuretics before randomization were independently associated with the occurrence of both events. Careful dose up-titration in these patients should be performed to minimize the occurrence and severity of these events.χ2HRP valueHypoSBP (10 mm Hg)25.180.66<0.0001Age (10 years)18.361.51<0.0001Weight (10 kg if <60 kg)14.540.300.0001C+V13.882.110.0002Potassium sparing diuretics at random12.582.410.0004Heart rate (10 BPM)11.571.290.0007RDCreatinine (10 mg/dL)124.101.36<0.0001Pulse press23.892.52<0.0001Potassium sparing diuretics at random13.212.970.0003

Do sudden cardiac death rates warrant earlier treatment following myocardial infarction? experience from the VALIANT Trial

Purpose: Patients with left ventricular ejection fraction (LVEF) ≤30% following myocardial infarction (MI) are at greater risk for sudden cardiac death (SCD). Current guidelines recommend implantable cardioverter defibrillator (ICD) placement in patients with EF ≤30% beyond 30 days post-MI. We determined the incidence and timing of SCD in a high-risk MI population. Methods: The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial enrolled 14,703 patients with left ventricular systolic dysfunction (LVSD), heart failure (HF), or both following MI (median 4.9 days post-MI, mean age 64.8 years, 31% women, mean EF 35.3%). SCD was defined as unexpected out-of-hospital death by a central committee. Results: EF was recorded in 11,338 patients. A total of 925 patients experienced SCD during the study. Of these, 634 occurred in the first year and 131 occurred within 30 days. Among patients with EF ≤30% (n = 2468), 335 had SCD in year 1 with 74 occurring ≤30 days. Of 5830 patients with EF 30–40%, 213 had SCD in year 1 with 38 occurring ≤30 days. Of 3040 patients with EF >40%, only 84 had SCD in the first year (Figure). Conclusions: More than half of the patients who had SCD post-MI had an EF <30%. In patients meeting current LVEF criteria for ICD, 22% had sudden death within 30 days of MI, suggesting a role for earlier implantation of ICD after MI.[figure1]

Increased risk of both mortality and morbidity with prior as well as current atrial fibrillation after myocardial infarction: results of VALIANT

Purpose: New-onset atrial fibrillation (AF) after myocardial infarction (MI) is associated with increased short-term mortality. The longer-term relationship between AF and both fatal and non-fatal outcomes is less well defined. Similarly, how the risk related to new-onset AF compares with that of pre-existing AF is unknown. Methods: The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial enrolled 14,703 patients with heart failure (HF), left ventricular systolic dysfunction (LVSD), or both after MI. AF status was assessed at presentation and again at randomization (median 4.9 days after symptom onset). ‘Current AF’ was defined as AF detected at any time from admission to randomization. Patients with a history of AF on admission but without ‘Current AF’ were defined as ‘Prior AF.’ The main outcomes were death and cardiovascular (CV) mortality/morbidity (CV death, MI, HF, stroke, or resuscitated sudden death) during a 3-year follow-up. The hazard ratio (HR) of AF was obtained from multivariable models including <70 covariates. Results: A total of 339 (2%) patients had prior AF, 1812 (12%) had current AF, and 12,509 (86%) patients had no AF. AF status was unknown in 43 patients. Current and Prior AF patients were older and more often women. They had more previous HF, angina, and MI but were less likely to receive a beta-blocker or thrombolytic treatment than those without AF. Patients with AF were more often in Killip class II or above than were patients without AF. Three-year mortality was 17% in patients without AF compared with 31% in current AF patients and 32% in prior AF patients. In a Cox regression multivariable model, compared with no AF, prior AF was associated with increased mortality (HR 1.25, 95% CI 1.03–1.52; P = 0.03), as was current AF (HR 1.32, 1.20–1.45; P<0.0001). The adjusted HR for CV mortality/morbidity with prior AF was 1.15 (0.98–1.35; P = 0.08) and 1.21 (1.12–1.31; P<0.0001) for current AF. Conclusions: Current and prior AF were associated with a higher long-term mortality and greater risk of adverse CV events after an MI complicated by HF and/or LVSD. Whether the risk associated with AF can be reversed with treatment is an important clinical question, as this arrhythmia occurs in a high proportion of these patients.

Heart failure post-myocardial infarction in the new millennium: how often does it occur, can we predict it, and what are the consequences?

Purpose: Patients (pts) with acute myocardial infarction (MI) complicated by pulmonary edema and/or depressed ejection fraction (EF) are at heightened risk for chronic heart failure (HF) and/or death. We utilized the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial experience to determine predictors of cardiovascular (CV) death and/or HF in high-risk MI pts undergoing modern therapy. Methods: VALIANT enrolled 14,703 pts with MI complicated by Killip class ≥2 and/or reduced EF between 0.5 and 10 days post-MI randomized to valsartan, captopril, or combination (median follow-up 24.7 months). Cox proportional hazards model was used to determine predictors of CV death and/or hospitalization for HF requiring intravenous therapy. Results: CV death occurred in 2484 (16.9%) pts, HF hospitalization in 2388 (16.2%), and 3992 (27%) died from CV cause and/or developed HF. Of the 2388 with HF hospitalization, 880 (36.9%) subsequently died. The most powerful independent predictors of HF and/or CV death were older age, higher baseline heart rate and diabetes mellitus (Table). There were no differences in outcomes between pts randomized to valsartan, captopril, or combination. Also, 73% (n=10,711) neither developed HF nor died from CV causes. Conclusion: Even among high-risk MI pts, the majority did not develop HF or die from CV causes. Age, diabetes, and rapid heart rate remain significant predictors of CV death and/or HF hospitalization. Mortality is twice as high among pts hospitalized for HF.VariableHazard Ratio (95% CI)Chi- squareVariableHazard Ratio (95% CI)Chi- squareAge (risk/10 years)1.35(1.30-1.40)256.9Prior MI1.33(1.24-1.46)54.8Heart rate (1 beat/min increase)1.02(1.01-1.02)172.8HF History1.34(1.24-1.46)49.6Diabetes mellitus1.48(1.37-1.59)112.9Pulse pressure (1 mm Hg increase)0.79(0.72-0.87)44.0BMI (1 kg/m2 increase)1.03(1.01-1.04)98.1Current smoker1.30(1.20-1.42)39.5Creatinine (0.1 mg/dL increase)1.05(1.04-1.07)95.2Hypertension History1.24(1.16-1.34)35.5Killip class (3 or 4)1.31(1.22-1.41)55.2Angioplasty Post-MI0.77(0.69-0.85)24.9

Angiotensin II receptor blockers in older patients.

Older patients with hypertension are often inadequately treated due to misconceptions regarding reasonable goal blood pressures or concerns about treatment side effects. Adequately treating hypertension can yield impressive benefits in terms of improved morbidity and enhanced quality of life in persons of any age. Antagonists of the renin-angiotensin-aldosterone system are especially effective in older persons, many of whom have concomitant conditions such as diabetes mellitus, renal dysfunction, and other cardiovascular risk factors. Treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been shown to improve many of the complications of hypertension, including left ventricular hypertrophy and renal disease. Results of recent key studies such as Losartan Intervention For Endpoint Reduction in Hypertension (LIFE), Valsartan in Heart Failure Trial (Val-HeFT), Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM), and Valsartan in Acute Myocardial Infarction (VALIANT) add to the evidence that angiotensin II receptor blockers are well suited for the treatment of hypertension in older patients. These trials also indicate that they are appropriate therapy for heart failure patients and for patients who have experienced acute myocardial infarction, particularly those who are unable to tolerate an angiotensin-converting enzyme inhibitor.

Valsartan

Valsartan (Diovan) is an oral angiotensin II-receptor antagonist with specificity for the angiotensin II type 1 receptor subtype. It demonstrates antihypertensive activity and slows the progression of chronic heart failure (CHF). Recently it has been evaluated in comparison with an ACE inhibitor regimen in patients with heart failure or left ventricular systolic dysfunction (LVSD) after an acute myocardial infarction (MI), a population known to be at high risk of subsequent death or other major cardiovascular events. In the VALIANT (VALsartan In Acute myocardial iNfarcTion) trial, valsartan was as effective as captopril at reducing mortality and cardiovascular morbidity in patients who developed heart failure and/or LVSD after surviving an MI. It was also generally well tolerated in this population. Treatment with a combination of valsartan plus captopril provided no additional therapeutic benefit over treatment with captopril and was less well tolerated. Valsartan has a potential role as a new treatment for high-risk patients in the post-MI setting.

VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context.

The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial compared outcomes with: (1) angiotensin-converting enzyme inhibition (ACEI) with the reference agent captopril; (2) angiotensin-receptor blockade (ARB) with valsartan; or (3) both in patients with heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) after myocardial infarction (MI). a goal of this active-control trial was to simulate conditions that would lead current practitioners to use ACEIs. Thus, we compared characteristics of VALIANT patients with those of patients in placebo-controlled trials that established ACEIs as standard treatment. We collected demographic, clinical, medication and imaging information from 14703 patients in 24 countries. This high-risk population was a median 65.8 years old, and 31.1% were female. Most (51.8%) showed imaging evidence of LVSD at enrollment. Most (72%) had Killip class>/=II HF. Patients received evidence-based therapies at rates similar to those of contemporary MI trials and at an improved rate compared with prior placebo-controlled ACEI trials. VALIANT represents the largest globally representative cohort enrolled with HF and/or LVSD after MI. Patients were similar to those in placebo-controlled ACEI trials while reflecting improvements in evidence-based care. With enrollment complete, VALIANT is poised to define the optimal strategy for renin-angiotensin system blockade after MI to improve cardiovascular outcomes.

Manipulation of the renin-angiotensin system.

Since the initial description of angiotensin II–mediated hypertension >40 years ago, basic and clinical investigations of the renin-angiotensin system (RAS) have resulted in a broader understanding of cardiovascular pathophysiology and significant advances in therapy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are now widely prescribed for the treatment of hypertension and left ventricular (LV) dysfunction; more recently, the aldosterone receptor antagonist, spironolactone, has proven beneficial in severe heart failure. This article will focus on our current understanding of the RAS and how pharmacological manipulation of this system can improve clinical outcomes in patients with cardiovascular disease. ### Pathophysiological Rationale for RAS Manipulation Renin is released by juxtuloglomerular cells in the kidney in response to renal hypoperfusion, decreased sodium delivery, and sympathetic activation (Figure 1). Angiotensinogen produced by the liver is cleaved by renin to yield the inactive decapeptide angiotensin I. Circulating angiotensin I is, in turn, converted to angiotensin II in the lungs by the action of ACE. ACE, or kininase II, also plays a key role in the kallikrein-kinin system by cleaving bradykinin to inactive peptides. In addition to the hormonal effects of circulating angiotensin II, all of the necessary components of the RAS exist in several organs and tissues, including the heart, kidneys, and vasculature. Figure 1. Pathophysiology of the RAS. SMC indicates smooth muscle cell. Angiotensin II exerts its actions in target organs and tissues by binding to both angiotensin II type 1 and 2 (AT1 and AT2) receptors, although adverse effects in humans seem to be mediated primarily by the AT1 receptor (Figure 1). In the kidney, angiotensin II causes sodium and water retention and efferent arteriolar vasoconstriction. Constriction of the systemic vasculature by angiotensin II causes hypertension, whereas coronary vasoconstriction may cause myocardial ischemia and arrhythmias. Angiotensin II–stimulated secretion of aldosterone by the adrenal cortex and arginine …