The Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) Trial: Rationale and Design

Background: Although 40% to 50% of patients with chronic heart failure (HF) have relatively preserved systolic function (PSF), few trials have been conducted in this population and treatment guidelines do not include evidence-based recommendations. Methods and Results: The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) is enrolling 4100 subjects with HF-PSF to evaluate whether 300 mg irbesartan is superior to placebo in reducing mortality and prespecified categories of cardiovascular hospitalizations. The principal inclusion criteria are age ≥60 years, heart failure symptoms, an ejection fraction ≥45%, and either hospitalization for heart failure within 6 months or corroborative evidence of heart failure or the substrate for diastolic heart failure. Additional secondary end points include cardiovascular mortality, cause-specific mortality and morbidity, change in New York Heart Association functional class, quality of life, and N-terminal pro-BNP measurements. Follow-up will continue until 1440 patients experience a primary end point. Substudies will evaluate changes in echocardiographic measurements and serum collagen markers. Conclusion: I-PRESERVE is the largest trial in this understudied area and will provide crucial information on the characteristics and course of the syndrome, as well as the efficacy of the angiotensin receptor blocker irbesartan

The Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) Trial: Rationale and Design

Background: Although 40% to 50% of patients with chronic heart failure (HF) have relatively preserved systolic function (PSF), few trials have been conducted in this population and treatment guidelines do not include evidence-based recommendations. Methods and Results: The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) is enrolling 4100 subjects with HF-PSF to evaluate whether 300 mg irbesartan is superior to placebo in reducing mortality and prespecified categories of cardiovascular hospitalizations. The principal inclusion criteria are age ≥60 years, heart failure symptoms, an ejection fraction ≥45%, and either hospitalization for heart failure within 6 months or corroborative evidence of heart failure or the substrate for diastolic heart failure. Additional secondary end points include cardiovascular mortality, cause-specific mortality and morbidity, change in New York Heart Association functional class, quality of life, and N-terminal pro-BNP measurements. Follow-up will continue until 1440 patients experience a primary end point. Substudies will evaluate changes in echocardiographic measurements and serum collagen markers. Conclusion: I-PRESERVE is the largest trial in this understudied area and will provide crucial information on the characteristics and course of the syndrome, as well as the efficacy of the angiotensin receptor blocker irbesartan

Irbesartan in patients with heart failure and preserved ejection fraction

Background: Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome. Methods: We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life. Results: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes. Conclusions: Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.)

Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies

OBJECTIVE: To evaluate the 104-week safety of dapagliflozin in older patients with type 2 diabetes mellitus. METHODS: Pooled analysis assessing general safety (nine phase III studies ≤104 weeks) and cardiovascular safety (21 phase IIb/III studies ≤208 weeks) by age (<65; ≥65; ≥75 years). Patients with type 2 diabetes mellitus (±background glucose-lowering therapy) received: dapagliflozin 10 mg (n = 2026) vs. placebo (n = 1956) (nine-study pool); or dapagliflozin (2.5–50 mg; n = 5936) vs. control (placebo/comparator) (n = 3403) (21-study pool). RESULTS: Adverse events (AEs) and discontinuations owing to AEs were more common in older vs. younger patients, and were more frequent with dapagliflozin than placebo (AEs: <65 years: 73.1 vs. 70.7 %; ≥65 years: 77.4 vs. 73.1 %; ≥75 years: 80.4 vs. 75.3 %, respectively; discontinuations: <65 years: 5.9 vs. 5.0 %; ≥65 years: 14.4 vs. 12.2 %; ≥75 years: 26.8 vs. 22.1 %, respectively); serious AE (SAE) frequency was similar (<65 years: 11.0 vs. 11.8 %; ≥65 years: 20.0 vs. 20.2 %; ≥75 years: 19.6 vs. 18.2 %, respectively). Hypoglycaemia frequency was similar across age groups and was higher with dapagliflozin than placebo (<65 years: 18.0 vs. 13.4 %; ≥65 years: 20.2 vs. 17.7 %; ≥75 years: 17.5 vs. 16.9 %, respectively); major episodes were rare. Urinary tract infection frequency was similar between treatment groups in older patients, with no increase vs. younger patients (<65 years: 8.8 vs. 5.5 %; ≥65 years: 8.1 vs. 7.6 %; ≥75 years: 8.2 vs. 9.1 %, respectively); urinary tract infection SAEs were rare. Genital infection AEs were more common with dapagliflozin, with no increase in older patients (<65 years: 8.2 vs. 1.0 %; ≥65 years: 6.6 vs. 0.9 %; ≥75 years: 7.2 vs. 0.0 %, respectively) and no SAEs. Volume reduction AEs were uncommon, with a higher frequency with dapagliflozin vs. placebo and in patients ≥75 years (<65 years: 1.7 vs. 1.2 %; ≥65 years: 2.3 vs. 1.7 %; ≥75 years: 3.1 vs. 2.6 %, respectively). Dapagliflozin did not increase the risk of fractures (<65 years: 1.1 vs. 1.1 %; ≥65 years: 1.1 vs. 2.7 %; ≥75 years: 1.0 vs. 2.6 %, respectively) or falls (<65 years: 0.7 vs. 0.7 %; ≥65 years: 0.6 vs. 2.1 %; ≥75 years: 0.0 vs. 1.3 %, respectively), regardless of age. AEs of renal function were more common with dapagliflozin than placebo and increased with age (<65 years: 3.5 vs. 2.3 %; ≥65 years: 14.0 vs. 7.9 %; ≥75 years: 29.9 vs. 20.8 %, respectively). Most were non-serious small transient increases in serum creatinine. Dapagliflozin did not increase cardiovascular risk regardless of age [hazard ratio (95 % confidence interval) vs. control: <65 years: 0.726 (0.473, 1.114); ≥65 years: 0.879 (0.565, 1.366); ≥75 years: 0.950 (0.345, 2.617), respectively]. CONCLUSION: Dapagliflozin treatment up to 104 weeks was well tolerated in older patients. Older dapagliflozin-treated patients had more renal AEs than placebo-treated patients; the majority of which were non-serious small transient changes in serum creatinine. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40266-016-0382-1) contains supplementary material, which is available to authorized users

The baseline characteristics of patients enrolled in the irbesartan in heart failure with preserved systolic function trial are similar to those in the community but differ from charm-preserved

Background: Although 40-50% of heart failure (HF) patients (Pts) have normal or near-normal left ventricular EF, this group is rarely included in clinical trials, in part because of difficulty in recruiting older predominantly female Pts. Methods: I-PRESERVE is a randomized placebo-controlled trial of irbesartan (target dose 300 mg qd) in 4,128 Pts with symptomatic HF, age ≥60 years with EF ≥45% who were hospitalized for HF within 6 months or had specified echo, ECG, or X-ray findings consistent with diastolic dysfunction and/or HF. The primary endpoint is a composite of all-cause mortality or protocol-specified cardiovascular hospitalizations for non-fatal myocardial infarction, stroke, HF, unstable angina or dysrhythmia. Results: 4,128 Pts were entered in 293 sites from 24 countries. Their characteristics are shown in the table, along with data collated from epidemiology and cohort studies and, for comparison, those from CHARM-Preserved, the only large trial that has sought to recruit a similar group. Among I-Preserve Pts, 44% had been admitted for HF within 6 months, 40% had X-ray pulmonary congestion, 30% had ECG LVH, and 85% had either echo LVH or left atrial enlargement. Mean N-terminal BNP levels (Roche assay) were 843 ± 1594 pg/ml, consistent with the HF diagnosis. At baseline, 84% were taking diuretics, 62% beta-blockers, 44% calcium blockers, 27% ACE inhibitors (enrollment on background ACE inhibitors limited to 30% by protocol), and 20% spironolactone. Conclusions: I-Preserve succeeded in enrolling a population similar to that described in epidemiology studies, including a predominance of older Pts and women with underlying hypertension and relative infrequent CAD. Also noteworthy are important differences in many of these characteristics compared to the CHARM population. Results are anticipated in 2007

Health related quality of life in I-PRESERVE trial

Purpose: Little is known about health-related quality of life (QHRQL) in patients with HF and preserved EF (HF-PEF). We studied the impact of HF-PEF on HRQL (and the determinants of HRQL in patients with HF-PEF) in the Irbesartan in Heart Failure with Preserved Systolic Function trial.&lt;p&gt;&lt;/p&gt; Methods: At baseline, 3,622 patients with an EF ≥ 45% from 25 countries completed the extensively studied and validated Minnesota Living with Heart Failure questionnaire (MLwHF), a 21 item disease-specific instrument. A summary score of 0–105 is possible, with a higher score reflecting worse HRQL. In order to examine relationships between pathophysiology, symptoms/signs and HRQL, NYHA class (see table), peripheral oedema (see table), EF (quartiles) and plasma concentration of NT proBNP (quartiles) were divided into 4 categories.&lt;p&gt;&lt;/p&gt; Results: Mean age was 72 (range 53–95) years and 61% were female. Mean MLwHF score was 42.4 (SD 20.7). There was no relationship between EF or NT proBNP and HRQL whereas NYHA class and oedema were strongly correlated with HROL.&lt;p&gt;&lt;/p&gt