6 ADVERSE REACTIONS
Serious adverse reactions reported in postmarket clinical trials include increased mortality and AKI (including need for RRT) in critically ill subjects, including subjects with sepsis, and surgical subjects. Clinical trials have also shown increased mortality and AKI in blunt trauma subjects. Increased coagulopathy was reported in surgical subjects.
Most common adverse reactions are hypersensitivity, coagulopathy, hemodilution, circulatory overload and metabolic acidosis.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
(Note: All of the studies listed below used licensed HES products except for reference 4.)
A randomized controlled trial (N=804) in severe sepsis patients using HES product (not approved in the U.S.) reported increased mortality (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03) and RRT (relative risk, 1.35; 95% CI, 1.01 to 1.80; p=0.04) in the HES treatment arm.4
Another randomized controlled trial (N=196) using different HES in severe sepsis patients reported no difference in mortality (relative risk, 1.20; 95% CI, 0.83 to 1.74; p=0.33) and a trend for RRT (relative risk, 1.83; 95% CI, 0.93 to 3.59; p=0.06) in HES patients.5
A randomized controlled trial (N=7000) using different HES in a heterogeneous patient population consisting of critically ill adult patients admitted to the ICU reported no difference in mortality (relative risk, 1.06; 95% CI, 0.96 to 1.18; p=0.26) but increased use of RRT (relative risk, 1.21; 95% CI, 1.00 to 1.45; p=0.04) in HES patients.6
In a retrospective study of adult patients (N=1442) undergoing pulmonary or esophageal surgery who were prophylactically fluid restricted during the procedure, 74 developed AKI (5.1%) within the first 72 hours postoperatively. Fluid restriction neither increased nor was a risk factor for AKI. AKI occurred more often when HES products were administered to patients with decreased renal function or having >2 risk factors with normal renal function, whereas restriction of crystalloid was unrelated to AKI, regardless of preoperative renal function.12
In a retrospective case series of high-risk adult vascular surgery patients (N=796) receiving fluid therapy during a vascular surgery procedure, logistic regression analysis using prespecified confounding variables or suspected risk factors for AKI showed that intraoperative administration of an HES product was associated with increased likelihood of 30-day mortality and need for RRT, compared with use of crystalloids alone.13
In a retrospective study of adult subjects undergoing elective noncardiac surgery, patients (N=14,680) receiving an HES product and crystalloid were propensity-matched with patients (N=14,680) receiving only crystalloid. After controlling for potential confounding variables, odds of experiencing AKI of severe intensity with HES was 21% greater than with crystalloid alone. In addition, AKI risk increased as a function of HES volume.14
In a prospective observational study assessing the impact of HES products on recipient renal graft outcomes in brain-dead organ donors, data were obtained on 986 kidneys transplanted from 529 donors. Kidneys from donors who received HES had a higher rate of delayed graft function in recipient subjects (41% versus 31%). After accounting for the propensity of donors to receive HES products, HES product administration was independently associated with an increased risk of delayed graft function in recipients. A dose response relationship also was evident.15
In a randomized, controlled trial of adult subjects (N=33) undergoing elective cystectomy comparing an HES product versus lactated Ringer's, administration of HES reduced clot strength (Maximum Amplitude; p<0.001) and increased blinded evaluation of perioperative blood loss by more than 50% (2181 mL versus 1370 mL, respectively; p=0.04). There was no significant between-group difference with respect to frequency of reoperation or length of hospital stay.16
In a prospective, sequential, observational study in adult subjects undergoing open heart surgery in association with cardiopulmonary bypass, fluid therapy using only an HES product (2004–2006, N=2137), 4% gelatin (2006–2008, N=2324) and crystalloids (N=2017, 2008–2010) led to increased need for renal replacement therapy after HES and gelatin, compared with crystalloid. Propensity score stratification confirmed greater use of RRT in the HES and gelatin periods compared to the crystalloid period. Fluid intake was higher in the crystalloid group only during the first 20 hours.17
In a retrospective observational study, 606 adult patients underwent open heart surgery in association with cardiopulmonary bypass. Until July 2013 they received an HES product (N=247) both as pump prime (1500 mL) and intraoperative fluid replacement (1000 mL), but only crystalloid (N=359) from August 2013 onward. The frequency (percent) of postoperative AKI was higher in patients receiving HES (N=53; 21.5%) than those receiving crystalloid (N=34; 9.5%). Surgical revision for rebleeding also was higher for HES (N=11; 4.6%) than for crystalloid (N=5; 1.4%).18
In a meta-analysis of RCTs (n=15) in adult subjects (N=4409) undergoing surgery who received an HES product, significantly more HES subjects (83/2157; 3.8%) than controls (56/2252; 2.5%) underwent RRT (relative risk, 1.44; 95% CI, 1.04, 2.01).19
In a retrospective observational study of adult blunt and penetrating trauma patients, use of an HES product was a significant independent predictor of AKI after blunt trauma, but not penetrating trauma, in multiple logistic regression analysis. In separate logistic regression models, HES also was a significant predictor of mortality after blunt trauma but not penetrating trauma.20
In a retrospective observational study of severely injured adult blunt (89%) and penetrating (11%) trauma patients (N=413) admitted to the ICU, 103 patients developed AKI within the first week of ICU admission. AKI was associated with increased 30-day (17.5% versus 5.8%, AKI versus non-AKI cohorts, respectively) and 1-year mortality (26.2% versus 7.1%). Univariate and multivariable regression analyses of prespecified risk factors for AKI found that volume loading using an HES product was independently associated with postinjury AKI within the first 24 hours.21
6.2 Postmarketing Experience
Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified and reported during the post-approval use of HES products:
including death, life-threatening anaphylactic/anaphylactoid reactions, cardiac arrest, ventricular fibrillation, severe hypotension, non-cardiac pulmonary edema, laryngeal edema, bronchospasm, angioedema, wheezing, restlessness, tachypnea, stridor, fever, chest pain, bradycardia, tachycardia, shortness of breath, chills, urticaria, pruritus, facial and periorbital edema, coughing, sneezing, flushing, erythema multiforme, and rash [see Warnings and Precautions (5.3)].
including circulatory overload, congestive heart failure, and pulmonary edema [see Warnings and Precautions (5.4)].
including intracranial bleeding, bleeding and/or anemia due to hemodilution [see Warnings and Precautions (5.4)] and/or Factor VIII deficiency, acquired von Willebrand's-like syndrome, and coagulopathy including rare cases of disseminated intravascular coagulopathy and hemolysis.
including metabolic acidosis.
including vomiting, peripheral edema of the lower extremities, submaxillary and parotid glandular enlargement, mild influenza-like symptoms, headaches, and muscle pains. Hydroxyethyl starch-associated pruritus has been reported in some patients with deposits of hydroxyethyl starch in peripheral nerves.