Paulette A. Lyle

Risk Scores for Predicting Outcomes in Patients with Type 2 Diabetes and Nephropathy: The RENAAL Study

Diabetic nephropathy is the most important cause of ESRD. The aim of this study was to develop a risk score from risk predictors for ESRD, with and without death, in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and to compare ability of the ESRD risk score and its components to predict ESRD. The risk score was developed from coefficients of independent risk factors from multivariate analysis of baseline variables and equals (1.96 x log [urinary albumin:creatinine ratio]) - (0.78 serum albumin [g/dl]) + (1.28 x serum creatinine [mg/dl]) - (0.11 x hemoglobin [g/dl]). It was robust with respect to severity of nephropathy, gender, race, and treatment group. The risk score for ESRD or death was comparable. The four risk predictors for progression of kidney disease were independent of therapy. For combined treatment groups, the hazard ratio between the fourth and first quartiles of the ESRD risk score was 49.0, as compared with the corresponding hazard ratios for each component: 14.7 for urinary albumin:creatinine ratio, 9.2 for serum creatinine, 5.5 for hemoglobin, and 10.2 for serum albumin. The RENAAL risk scores for ESRD with or without death emphasize the importance of identification of level of albuminuria, serum albumin, serum creatinine, and hemoglobin to predict development of ESRD in patients with type 2 diabetes and nephropathy. Although albuminuria is a strong risk factor for ESRD, the contribution of serum albumin, serum creatinine, and hemoglobin level further enhances prediction of ESRD. Future trials with a similar patient population and outcomes measures should consider adjusting analyses for baseline risk factors.

Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy: The RENAAL study

Diabetic nephropathy is the most important cause of ESRD. The aim of this study was to develop a risk score from risk predictors for ESRD, with and without death, in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study and to compare ability of the ESRD risk score and its components to predict ESRD. The risk score was developed from coefficients of independent risk factors from multivariate analysis of baseline variables and equals (1.96 x log [urinary albumin:creatinine ratio]) - (0.78 serum albumin [g/dl]) + (1.28 x serum creatinine [mg/dl]) - (0.11 x hemoglobin [g/dl]). It was robust with respect to severity of nephropathy, gender, race, and treatment group. The risk score for ESRD or death was comparable. The four risk predictors for progression of kidney disease were independent of therapy. For combined treatment groups, the hazard ratio between the fourth and first quartiles of the ESRD risk score was 49.0, as compared with the corresponding hazard ratios for each component: 14.7 for urinary albumin:creatinine ratio, 9.2 for serum creatinine, 5.5 for hemoglobin, and 10.2 for serum albumin. The RENAAL risk scores for ESRD with or without death emphasize the importance of identification of level of albuminuria, serum albumin, serum creatinine, and hemoglobin to predict development of ESRD in patients with type 2 diabetes and nephropathy. Although albuminuria is a strong risk factor for ESRD, the contribution of serum albumin, serum creatinine, and hemoglobin level further enhances prediction of ESRD. Future trials with a similar patient population and outcomes measures should consider adjusting analyses for baseline risk factors.

ACE Gene Polymorphism and Losartan Treatment in Type 2 Diabetic Patients With Nephropathy

Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.

Clusters of metabolic risk factors predict cardiovascular events in hypertension with target-organ damage: the LIFE study

The relation of metabolic syndrome (MetS) with cardiovascular outcome may be less evident when preclinical cardiovascular disease is present. We explored, in a post hoc analysis, whether MetS predicts cardiovascular events in hypertensive patients with electrocardiographic left ventricular hypertrophy (ECG-LVH) in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study. MetS was defined by ⩾2 risk factors plus hypertension: body mass index ⩾30 kg/m2, high-density lipoprotein (HDL)-cholesterol <1.0/1.3 mmol/l (<40/50 mg/dl) (men/women), glucose ⩾6.1 mmol/l (⩾110 mg/dl) fasting or ⩾7.8 mmol/l (⩾140 mg/dl) nonfasting or diabetes. Cardiovascular death and the primary composite end point (CEP) of cardiovascular death, stroke and myocardial infarction were examined. In MetS (1591 (19.3%) of 8243 eligible patients), low HDL-cholesterol (72%), obesity (77%) and impaired glucose (73%) were similarly prevalent, with higher blood pressure, serum creatinine and Cornell product, but lower Sokolow–Lyon voltage (all P<0.001). After adjusting for baseline covariates, hazard ratios for CEPs and cardiovascular death (4.8±1.1 years follow-up) were 1.47 (95% confidence interval (CI), 1.27–1.71)- and 1.73 (95% CI, 1.38–2.17)-fold higher with MetS (both P<0.0001), and were only marginally reduced when further adjusted for diabetes, obesity, low HDL-cholesterol, non-HDL-cholesterol, pulse pressure and in-treatment systolic blood pressure and heart rate. Thus, MetS is associated with increased cardiovascular events in hypertensive patients with ECG-LVH, independently of single cardiovascular risk factors.

Effect of ACE insertion/deletion and 12 other polymorphisms on clinical outcomes and response to treatment in the life study

Objective This pharmacogenetics substudy from the Losartan Intervention for Endpoint reduction in Hypertension study in patients with hypertension and left ventricular hypertrophy (LVH) treated with the angiotensin receptor blocker losartan versus the &bgr;-blocker atenolol for 4.8 years tested whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and 12 other previously well-characterized polymorphisms of hypertension susceptibility genes affected blood pressure reduction, heart rate reduction, cardiovascular events, and/or response to treatment. These polymorphisms were chosen because they could affect blood pressure control or the pharmacological action of losartan or atenolol. Methods We genotyped 3503 patients, 1774 on losartan and 1729 on atenolol. Results ACE and the 12 other genotypes did not affect the reduction in systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, or heart rate, or treatment differences between losartan and atenolol on these endpoints, as assessed by general linear models. Also, ACE and the 12 other genotypes did not affect risk of the primary composite endpoint or its components stroke, myocardial infarction, and cardiovascular death, or treatment differences between losartan and atenolol on these endpoints, as assessed by Cox proportional hazards models including baseline Framingham risk score and LVH. Conclusion ACE insertion/deletion and 12 other polymorphisms of hypertension susceptibility genes did not affect blood pressure reduction, heart rate reduction, or cardiovascular events in patients with hypertension and LVH, or treatment differences between losartan and atenolol on these endpoints. These results suggest that the observed effects of losartan versus atenolol in the Losartan Intervention for Endpoint reduction in hypertension study do not depend on ACE and 12 other polymorphisms of hypertension susceptibility genes.

The effect of baseline physical activity on cardiovascular outcomes and new-onset diabetes in patients treated for hypertension and left ventricular hypertrophy: the LIFE study

Objectives.  Physical activity (PA) is a preventive strategy for cardiovascular disease and for managing cardiovascular risk factors. There is little information on the effectiveness of PA for the prevention of cardiovascular outcomes once cardiovascular disease is present. Thus, we studied the relationship between PA at baseline and cardiovascular events in a high‐risk population.

Pulse Pressure and Effects of Losartan or Atenolol in Patients With Hypertension and Left Ventricular Hypertrophy

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, the primary composite end point of cardiovascular death, stroke, and myocardial infarction was reduced by losartan versus atenolol in patients with hypertension and left ventricular hypertrophy. The objective of this post hoc analysis was to determine the influence of pulse pressure on outcome. Patients were divided into quartiles of baseline pulse pressure. Cox regression, including baseline Framingham risk score as a covariate, was used to compare risk in the quartiles. In the atenolol group, there were significantly higher risks in the highest versus lowest quartile for the composite end point 28% (confidence interval [CI], 2% to 62%; P=0.035), stroke 84% (CI, 32% to 157%; P<0.001), and total mortality 41% (CI, 7% to 84%; P=0.013). Risk for myocardial infarction was 44% higher (CI, −5% to 120%; P=0.089). The risks in the losartan group also increased with increasing quartile, but were lower than in the atenolol group, and differences between the highest and lowest quartiles were not significant: composite end point 12% (CI, −13% to 44%; P>0.2), stroke −5% (CI, −34% to 37%; P>0.2), myocardial infarction 30% (CI, −13% to 94%; P>0.2), and total mortality 32% (CI, −1% to 76%; P=0.062). In patients with hypertension and left ventricular hypertrophy in the LIFE study, there were significantly higher risks, adjusted for the Framingham risk score, for the primary composite end point, stroke, and total mortality in the highest versus lowest quartile of pulse pressure with atenolol-based treatment. The risks in the losartan group also increased with increasing pulse pressure quartile, but were lower than those in the atenolol group, and were not significant.

Effects of Losartan in Women With Hypertension and Left Ventricular Hypertrophy Results From the Losartan Intervention For Endpoint Reduction in Hypertension Study

Hypertension is a risk factor for cardiovascular disease and outcomes in women. These posthoc analyses from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study evaluated losartan- versus atenolol-based therapy on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and other end points in 4963 women. Fewer events occurred in women versus men. Women in the losartan group had significant reductions in the primary end point (215 [18.2 per 1000 patient-years] versus 261 [22.5 per 1000 patient-years]; hazard ratio [HR]: 0.82 [95% CI: 0.68 to 0.98]; P=0.031), stroke (109 versus 154; HR: 0.71 [95% CI: 0.55 to 0.90]; P=0.005), total mortality (HR: 0.77 [95% CI: 0.63 to 0.95]; P=0.014), and new-onset diabetes (HR: 0.75 [95% CI: 0.59 to 0.94]; P=0.015) versus the atenolol group, with no between-treatment difference for myocardial infarction (HR: 1.02 [95% CI: 0.74 to 1.39]; P=0.925), cardiovascular mortality (HR: 0.86 [95% CI: 0.64 to 1.14]; P=0.282), or hospitalization for heart failure (HR: 0.94 [95% CI: 0.68 to 1.28]; P=0.677). More women in the losartan group required hospitalization for angina (HR: 1.70 [95% CI: 1.16 to 2.51]; P=0.007). Risk reductions for the primary composite end point, stroke, total mortality, and new-onset diabetes were significantly greater with losartan- versus atenolol-based treatment in women with hypertension and left ventricular hypertrophy in the LIFE study. The risk reductions for losartan, along with the tests for the interaction of treatment and gender, indicated that the treatment effect was consistent in men and women for all of the end points tested, with the exception of hospitalization for angina.

The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study reported that a losartan‐based antihypertensive regimen reduced cardiovascular morbidity and mortality (composite of cardiovascular death, stroke, and myocardial infarction) more than therapy based on atenolol in patients with left ventricular hypertrophy and isolated systolic hypertension (ISH). Patients aged 55–80 years with blood pressures 160–200/<90 mm Hg were followed for a mean of 4.7 years. Blood pressure was similarly reduced in the losartan (n=660) and atenolol (n=666) ISH groups. There were 88 (6.6%) patients who experienced a stroke, 18 of which were fatal. Of patients experiencing strokes, 72.7% had an ischemic stroke. ISH patients in LIFE compared to the non‐ISH group had a higher incidence of any stroke and embolic stroke, and similar incidences of fatal, atherosclerotic, and hemorrhagiclother strokes. The incidence of any stroke (40% risk reduction [RR], p=0.02), fatal stroke (70% RR, p=0.035), and atherothrombotic stroke (45% RR, p=0.022) was significantly lower in losartan‐treated compared to the atenolol‐treated patients. The 36% RR for embolic strokes in the losartan group was not statistically significantly (p=0.33) different from the atenolol group. These data suggest that losartan‐based treatment is more effective than an atenolol‐based treatment for patients with ISH and a high risk for stroke.

A multicenter, randomized, double-blind, placebo-controlled, 8-week trial of the efficacy and tolerability of once-daily losartan 100 mg/hydrochlorothiazide 25 mg and losartan 50 mg/hydrochlorothiazide 12.5 mg in the treatment of moderate-to-severe essential hypertension.

BACKGROUND Many patients with moderate-to-severe hypertension require multiple drug therapy to achieve blood-pressure goals. Fixed-dose combination therapy with losartan and hydrochlorothiazide may be useful in this population. OBJECTIVE This study was conducted to obtain additional data on the antihypertensive efficacy and tolerability of once-daily, fixed-dose combinations of losartan and hydrochlorothiazide. METHODS This was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Patients > or = 21 years of age with moderate-to-severe essential hypertension, defined as a mean trough sitting diastolic blood pressure (SiDBP) of 105 to 115 mm Hg, were randomly assigned in a 2:2:1 ratio to receive losartan 100 mg/hydrochlorothiazide 25 mg (L100/25), losartan 50 mg/hydrochlorothiazide 12.5 mg (L50/12.5), or placebo (PBO) once daily for 8 weeks. The primary efficacy measurement was the mean change from baseline in trough SiDBP in the L100/25 versus L50/12.5 treatment groups. Responders were defined as patients with mean trough SiDBP <90 mm Hg or a > or = 10-mm Hg decrease in mean trough SiDBP. RESULTS A total of 446 patients were randomly assigned to receive L100/25 (n = 173), L50/12.5 (n = 184), or PBO (n = 89). At week 8, mean trough SiDBP was significantly lower than at baseline in the L100/25 (-17.5 mm Hg), L50/12.5 (-15.2 mm Hg), and PBO groups (-8.5 mm Hg) (all P < 0.001). The difference between the active-treatment groups was statistically significant (-2.2 mm Hg; 95% Cl, range -3.8 to -0.6) (P = 0.006), as was the difference between the L100/25 and PBO groups (-9.0 mm Hg; 95% CI, range -I1.0 to -7.0) (P < 0.001) and the L50/12.5 and PBO groups (-6.7 mm Hg; 95% CI, range -8.7 to -4.8) (P < 0.001). At week 8, the percentages of responders were 86.7% (144 of 166), 78.9% (142 of 180), and 50.0% (42 of 84) in the L100/25, L50/12.5, and PBO groups, respectively. The incidence of adverse experiences (AEs) was 34.7% (60 of 173) in the L100/25 group, 23.9% (44 of 184) in the L50/12.5 group, and 32.6% (29 of 89) in the PBO group. The incidence of drug-related AEs was similar among the treatment groups (L100/25, 7.5% [13 of 173]; L50/12.5, 7.1% [13 of 184]; and PBO, 11.2% [10 of 89]). CONCLUSIONS This study demonstrates the antihypertensive efficacy and tolerability of the once-daily, fixed-dose combination L50/12.5 in patients with moderate-to-severe essential hypertension. In this study, L100/25 provided additional anti-hypertensive efficacy beyond that of L50/12.5 (and both were more efficacious than PBO). Approximately 4 of 5 patients (78.9%) treated with L50/12.5 responded to therapy, as did nearly 9 of 10 patients (86.7%) treated with L100/25. The tolerability profiles of L50/12.5 and L100/25 were similar to that of PBO.