Presentation on theme: "Hypotension in Acute Decompensated Heart Failure: Findings from ASCEND-HF Background Context: Transient, in-hospital hypotension while hospitalized for."— Presentation transcript:
Hypotension in Acute Decompensated Heart Failure: Findings from ASCEND-HF Background Context: Transient, in-hospital hypotension while hospitalized for acute decompensated heart failure (ADHF) causes clinical concern, but contributing factors and its association with outcomes are poorly understood. Low blood pressure at the time of hospital admission for ADHF is a well-established risk factor for adverse cardiovascular outcomes, including re-hospitalization and mortality 1. However, only an estimated 25% of patients hospitalized with ADHF have low blood pressure at the time of hospital admission 2. While fall in systolic blood pressure during hospitalization for ADHF is associated with worsening renal function 3,4, it is unclear if transient changes in systolic blood pressure are directly associated with cardiovascular outcomes. ASCEND-HF: The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) was a double-blind, multi- national randomized control trial comparing outcomes among ADHF patients randomized to nesiritide or placebo 5. The ASCEND-HF overall results showed no mortality difference among those treated with nesiritide vs. placebo. However, use of nesiritide was strongly associated with in-hospital hypotension in ASCEND-HF. We performed a secondary analysis of ASCEND-HF to examine patient factors associated with hypotension and its effects on subsequent 30-day outcomes. Priyesh A. Patel a, Gretchen Heizer a, Phillip J. Schulte a, Christopher M. O’Connor b, Kenneth Dickstein c, Justin A. Ezekowitz d, Vic Hasselblad a, Barry M. Massie e, Roger M. Mills f, John J. McMurray g, Randall C. Starling h, W. H. Wilson Tang h, Robert M. Califf a,b, Adrian F. Hernandez a,b a Duke Clinical Research Institute, Durham, North Carolina, USA; b Duke University Medical Center, Durham, North Carolina, USA; c Stavanger University Hospital, Stavanger, Norway; d Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada; e University of California San Francisco and San Francisco Veterans Affairs Hospital, San Francisco, California, USA; f Janssen Research & Development, LLC, Raritan, New Jersey, USA; g Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; h Cleveland Clinic Foundation, Cleveland, Ohio, USA Contact Information Priyesh A. Patel, M.D. Fellow, Duke Clinical Research Institute firstname.lastname@example.org Disclosures PA Patel, G Heizer, PJ Schulte, K Dickstein, V Hasselblad, JJ McMurray, and WH Tang report no relevant disclosures. CM O’Connor reports consulting fees from Novella, Cardiology Consulting Associates, and Amgen, ownership/partnership/principal in Biscardia, LLC, and research support from Otsuka, Roche Diagnostics, BG Medicine, Critical Diagnostics, Astellas, Gilead, GE Healthcare, and ResMed. JA Ezekowitz reports consulting fees from Astra-Zeneca, Pfizer, Abbott Labs, Servier, and Bristol-Meyers-Squibb and research support from Amgen. BM Massie reports consulting fees from Novartis, Johnson and Johnson, Bristol- Meyers-Squibb, Merck, and Sorbent. RM Mills reports salary support from Johnson and Johnson Pharmaceutical Research and Development, LLC. RC Starling reports consulting fees from Novartis, BioControl, and Medtronic, ownership/patnership/principal in Cardiomems, research support from the National Institutes of Health, Medtronic, Biotronik, Novartis, and Thoratec, and receipt of benefits from the American Board of Internal Medicine. RM Califf reports consulting fees from KOWA, Eli Lilly, Glaxo Smith-Kline, WebMD, Bristol-Myers- Squibb, Nitrox LLC, Bayer, Orexigen Therapeutics, Sanofi-Aventis, Medtronic, Boehringer Ingelheim, and Gilead and research support from BMS, Roche, Merck, Novartis, Scios/Johnson and Johnson, Amilyn, Bristol-Myers-Squibb, and Bayer. AF Hernandez reports consulting fees from Sanofi, Johnson and Johnson, AstraZeneca, and Corthera and research support from Amylin and Scios/Johnson and Johnson. Methods Study Population : 7,141 patients with ADHF were randomized to nesiritide or placebo within 24 hours of first IV therapy. Clinical and laboratory data were recorded for all patients. Key inclusion criteria: dyspnea at rest or minimal activity + one or more accompanying signs (respiratory rate ≥20 breaths/minute or pulmonary congestion or edema with rales one-third or greater up the lung fields) + one or more objective measures of heart failure (congestion or edema on chest radiograph, BNP ≥400pg/mL or N-terminal pro-BNP ≥1000pg/mL, PCWP >20mm HG, or LVEF <40% in previously 12 months). Key exclusion criteria: “high risk” of hypotension (systolic pressure <100 mm Hg or 110 mm Hg with use of intravenous nitroglycerin), contraindications for vasodilators, unstable dose of IV vasoactive medications, milrinone or levosimendan therapy in the prior 30 days, and dobutamine treatment at ≥5mcg/mg/min. Defining Hypotension: Hypotension was reported at the discretion of the investigator. The threshold for reporting was based on individual investigator’s clinical judgment. Lowest blood pressure (BP), time of hypotension, and whether the episode was symptomatic vs. asymptomatic was recorded for the first episode of hypotension occurring before hospital discharge. Patients with missing data regarding episodes of hypotension or who died without an episode of hypotension were classified as having “no hypotension”. For patients with both symptomatic and asymptomatic hypotension, only data from the first event was utilized. Statistical Analysis: Baseline characteristics were compared using the Wilcoxon Rank-Sum test for continuous variables and the chi-square test for categorical variables. Stepwise logistic regression was used to assess the association of baseline factors with the risk of developing in-hospital hypotension. Candidate variables were based on clinical review of prior publications. A time-dependent Cox proportional hazards model was used to evaluate the association of in- hospital hypotension and 30-day outcomes. The model was adjusted for variables previously found to be associated with risk of these outcomes in the ASCEND-HF cohort (Table 1). The interaction of nesiritide on hypotension and 30-day outcomes was assessed to determine if randomization to nesiritide therapy altered the association between hypotension and 30-day outcomes. Missing baseline data had values imputed using Markov Chain Monte Carlo and regression methods. Final estimates and associated standard errors reflect the combined analysis over twenty-five imputed data sets. ResultsConclusions Prior studies have shown that low blood pressure at the time of hospitalization for ADHF is associated with poor 30-day outcomes. Our study is novel because we show that hypotension while hospitalized for ADHF is an independent prognostic factor for adverse 30- day outcomes among a population that was not hypotensive on hospital admission. Episodes of in-hospital hypotension were common among the ASCEND-HF population, and the majority were asymptomatic. While randomization to nesiritide therapy was strongly associated with in-hospital hypotension, it had no interaction with the relationship between time-dependent in-hospital hypotension and the three outcomes tested. This suggests that in-hospital hypotension may be associated with adverse outcomes regardless of cause. Severity of heart failure (orthopnea and S3 gallop, chronic metolazone therapy) and region were among other variables associated with hypotension. Regional variation in practice patterns and outcomes warrants further investigation. Chronic bumetanide therapy and pre- randomization calcium channel blocker use were among variables less likely to be associated with hypotension. Interestingly, smaller proportions of patients experiencing in- hospital hypotension had pre-randomization IV vasodilator therapy or nesiritide bolus, suggesting investigator bias against the use of vasoactive therapies among patients with more severe heart failure. Limitations: This is an observational, secondary analysis of ASCEND-HF, which was not specifically designed to study the relationship between hypotension and outcomes. No causality can be proven. These results are hypothesis-generating. Also, we attempted to adjust for confounding variables in our outcome models, but all confounding factors may not have been identified, thereby affecting our results. Variable Overall trial (N=7,141) No hypotension (n=5586) Hypotension (n=1555) p-value Female Sex34.2 34.433.8 0.664 Age67 (56, 76) 67 (55, 77) 0.681 Race 0.063 White55.955.258.4 Black15.115.414.1 Asian24.825.322.8 Region <0.001 North America45.443.651.8 Asia Pacific24.725.222.9 Latin America9.3 9.4 Central Europe13.515.27.6 Western Europe220.127.116.11 Medical History Hypertension72.174.065.5<0.001 Atrial fibrillation37.436.839.7 0.040 Ventricular tachycardia18.104.22.168<0.001 Diabetes mellitus42.744.137.6<0.001 Measurements Weight, kg78 (64, 95)78.7 (65, 95.4)76 (62.6, 92.2)<0.001 Temperature (C)36.6 (36.3, 36.9)36.6 (36.3, 36.8)36.6 (36.2, 36.9) 0.186 Baseline Systolic BP (mmHg)123 (110, 140)126 (112, 140)115 (105, 130)<0.001 Baseline Diastolic BP (mmHg)74 (66.0, 83.0)75 (68, 85)70 (63, 80)<0.001 Heart Rate (bpm)82 (72, 95)82 (71, 95)82 (73, 95) 0.065 BNP (pg/mL)990 (544,1850)962 (530,1820)1103 (597, 1968) 0.012 NT-pro-BNP (pg/mL)4501 (2098, 9177)4461 (2110, 9229)4771 (2041, 9081) 0.828 Creatinine (mg/dL)1.2 (1.0, 1.6) 1.2 (1.0, 1.5) 0.598 BUN (mg/dL)25.8 (18.0, 39.1)25.3 (18.0, 38.1)26.1 (18.0, 41.1) 0.036 Baseline Sodium (mmol/L)139 (136, 141) 138 (135, 141)<0.001 Ejection Fraction ≤ 40%79.378.582.1 0.002 Characteristics Orthopnea76.975.980.7<0.001 JVD, MVR, or S3 gallop70.569.175.2<0.001 Baseline Medications ACE-I or ARB60.860.262.9 0.056 Beta-blocker58.257.361.7 0.002 Aldosterone antagonist27.927.030.9 0.003 Calcium-channel blocker12.914.09.2<0.001 Chronic bumetanide22.214.171.124 0.342 Chronic metolazone126.96.36.199<0.001 Pre-randomization IV vasodilator 14.815.412.7 0.007 Planned In-hospital treatment (ITT) <0.001 Randomization to Nesiritide49.946.562.2 Bolus dose of Nesiritide60.764.248.0<0.001 Descriptive Characterization of Hypotensive Episodes Symptomatic BP: median 80mmHg, IQR 70-87mmHg Asymptomatic BP: median 83mmHg, IQR 79-88mmHg Time to hypotension: median 17.2 hours (IQR 5.2-30.8 hours) Table 2: Baseline Univariate Characteristics of Study Population Variable Odds Ratio Confidence Interval p-value Age (per 10 years over age >60)1.011.01-1.02<0.001 Measurements Temperature >36.4C(for each degree >36.4C)1.381.12-1.720.003 SBP ≤120 mmHg (per each 5 mmHg increase)0.95 0.95-0.96 <0.001 SBP >120 mmHg (per each 5 mmHg increase)0.980.98-0.99<0.001 Heart Rate ≤ 75 beats/minute (per 5 beats)1.021.01-1.030.001 Baseline Sodium ≤ 145mmol/L (per each 5mmol)/L decrease) 1.03 1.01-1.04 <0.001 Characteristics Baseline orthopnea1.311.13-1.520.001 Baseline S3 gallop1.211.06-1.400.006 Region (compared to North America) Asia Pacific0.630.54-0.74<0.001 Central Europe0.490.39-0.61<0.001 Latin America0.780.63-0.970.025 Western Europe1.070.85-1.350.556 Medications Randomization to nesiritide1.981.76-2.23<0.001 Chronic bumetanide0.520.35-0.780.002 Pre-rand Calcium-channel blocker0.700.57-0.85<0.001 Chronic metolazone1.741.17-2.600.007 Table 3: Results of a Multi-variable Associative Model* for In-Hospital Hypotension in ADHF Table 4: Association between In-hospital Hypotension and 30-day Outcomes Outcome Total N (% of total population without missing data) No hypotension n (% of No hypotension patients with outcome) Hypotension n (% of Hypotension patients with outcome) Hazard Ratio Confidence Interval Cox HR p- value 30-day mortality 273/7118 (3.8) 162/5565 (2.9) 111/1553 (7.1)2.031.57-2.61<0.001 30-day mortality or HF rehospitalization 686/6938 (9.9) 455/5422 (8.4) 231/1516 (15.2) 1.581.34-1.86<0.001 30-day mortality or all-cause hospitalization 1067/6942 (15.4) 747/5424 (13.8) 320/1518 (21.1) 1.401.22-1.61<0.001 Test for interaction of nesiritide on relationship of in-hospital hypotension and 30-day outcomes: 30-day mortality, p=0.874; 30-day mortality/HF hospitalization, p=0.908; 30- day mortality/all-cause hospitalization, p=0.238 30-day mortality30-day mortality/HF hospitalization30-day mortality/All-cause hospitalization Age BUN Sodium Systolic Blood Pressure Dyspnea with Minimal ExertionCreatinine Cerebrovascular Disease Depression Hospitalization in the Last Year Elevated JVP Chronic Respiratory Disease Dyspnea with Minimal ExertionBaseline Weight Table 1: Adjustment Variables for 30-day Outcome Models *C-statistic = 0.708 Values represent percentages or medians (interquartile range). 1 Am Heart J. 2008. Oct;156(4):662-73. 2 JAMA. 2006. Nov 8;296(18):2217-26. 3 Eur J Heart Fail. 2011 Sep;13(9):961-7. 4 Eur J Heart Fail..2011 Aug;13(8):877-84.. 5 N Engl J Med. 2011 Jul 7;365(1):32-43.