Search

Key Clinical Message: Transcatheter aortic valve implantation (TVAI) is a widely used treatment modality for severe aortic stenosis. The complication rates of the procedure have gradually decreased over time, owing to the improvements in procedural skills and development of TVAI devices. However, several rare but serious complications can still occur after TAVI. We recently encountered acute decompensated heart failure as a rare and fatal complication of TAVI and would like to share our experience. [ABSTRACT FROM AUTHOR]

Background: Speckle tracking-derived global longitudinal strain (GLS) of left ventricle is a potent prognostic marker for patients with ST-segment elevation myocardial infarction (STEMI). The purpose of this study was to investigate the difference of prognostic impact of GLS between anterior and nonanterior myocardial infarction. Methods: This study included 686 patients who underwent primary percutaneous coronary intervention for their first STEMI between November 2007 and April 2012. Differences in the prognostic impact of GLS between anterior MI group and nonanterior MI group were evaluated. The composite of all-cause mortality and hospitalization for heart failure in 2 years was investigated for outcome. Results: During the follow-up period, 77 (11.2%) adverse events occurred. The anterior and nonanterior MI groups included 339 and 347 patients, respectively. Among patients with anterior MI, GLS significantly predicted 2-year outcome in an adjusted model (adjusted hazard ratio [HR] 1.186; 95% confidence interval [CI] 1.071-1.314, P = 0.001), whereas the association between GLS and mortality was weaker in the nonanterior MI group (adjusted HR 0.977; 95% CI 0.884-1.081, P = 0.657). The interaction between the infarction territory and GLS was significant (P for interaction = 0.018), indicating that GLS was a more sensitive predictor of mortality in patients with anterior MI than that in those with nonanterior MI. Conclusions: Speckle tracking-derived GLS of left ventricle more sensitively predicted clinical outcome in patients with anterior MI than in those with nonanterior MI. [ABSTRACT FROM AUTHOR]

Purpose A new antihypertensive drug that selectively blocks angiotensin II receptor type 1, fimasartan, has a potent and rapidly acting antihypertensive effect. We investigated the antihypertensive effects of fimasartan 60 and 120 mg and its safety in comparison to 8 mg of candesartan. Methods This clinical trial is a multicenter, randomized, double-blind, active comparator, and parallel group study. Three hundred sixty-two individuals were screened, and 290 patients aged 19 to 75 years with mild to moderate hypertension (diastolic blood pressure [DBP], 90–110 mm Hg) were randomly assigned to 60 to 120 mg/d of fimasartan or 8 mg/d of candesartan after a 2-week placebo run-in period. Treatments were administered for 12 weeks without dosage adjustment. The primary end point was the differences in DBP changes at week 12. Findings After 12 weeks of treatment, DBP and systolic blood pressure (SBP) decreased significantly in all 3 groups. The decrease in DBP at week 12 was larger but not statistically significant in the fimasartan 60 mg compared with the candesartan 8 mg group with a mean (SD) difference of 1.72 (8.32) mm Hg (95% CI, −0.71 to 4.15 mm Hg; P = 0.17). The lower margin of the CI (−0.71 mm Hg) exceeded the noninferiority margin (−3.5 mm Hg). The DBP-lowering effect of fimasartan 120 mg was also nonsignificantly larger than candesartan 8 mg (difference, 1.58 [8.27] mm Hg; P = 0.20). The decrease in SBP was also nonsignificantly larger in the fimasartan 60 mg group compared with the candesartan 8 mg group (difference, 3.50 [12.63] mm Hg; P = .06). The SBP-lowering effect of fimasartan 120 mg was statistically larger than candesartan 8 mg (difference, 4.98 [13.99] mm Hg; P = .02). Response rate (DBP <90 mm Hg or DBP lowering >10 mm Hg at week 12) was also nonsignificantly greater in both fimasartan groups (Fimasartan 60 mg, 81%; fimasartan 120 mg, 72%; candesartan 8 mg, 71%). The safety profile of the fimasartan 60 mg and 120 mg was similar to candesartan 8 mg, with a slightly higher, but statistically not significant, incidence of hepatic enzyme elevation in fimasartan 120 mg. Implications The antihypertensive effect of fimasartan, a newly available angiotensin II receptor type 1 blocker, is comparable, although not superior, to candesartan with a good safety profile. ClinicalTrials.gov identifier: NCT01135212. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the association between serum high-sensitivity C-reactive protein (hs-CRP) and incident hypertension. Study subjects were 452 Koreans who were enrolled in a cohort study. Log-transformed hs-CRP (odds ratio, 1.89; 95% confidence interval, 1.05-3.39; p = 0.035) was an independent predictor of incident hypertension. Inclusion of hs-CRP showed significant increase in the area under the curve from 0.697 to 0.720 ( p = 0.042), the net reclassification improvement (0.394, p < 0.001) and integrated discrimination improvement (0.0111, p = 0.045). The hs-CRP added incremental value to the combination of systolic blood pressure and conventional risk factors in predicting incident hypertension. [ABSTRACT FROM AUTHOR]

Imaging modalities for percutaneous coronary intervention (PCI), such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), have increased in the current PCI era. However, their clinical benefits in acute myocardial infarction (AMI) have not been fully elucidated. This study investigated the long-term outcomes of image-guided PCI in patients with AMI using data from the Korean Acute Myocardial Infarction Registry. A total of 9,271 patients with AMI, who underwent PCI with second-generation drug-eluting stents between November 2011 and December 2015, were retrospectively examined, and target lesion failure (TLF) at 3 years (defined as the composite of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization) was evaluated. From the registry, 2,134 patients (23.0%) underwent image-guided PCI (IVUS-guided: n = 1,919 [20.6%]; OCT-guided: n = 215 patients [2.3%]). Based on propensity score matching, image-guided PCI was associated with a significant reduction in TLF (hazard ratio: 0.76; 95% confidence interval: 0.59–0.98, p = 0.035). In addition, the TLF incidence in the OCT-guided PCI group was comparable to that in the IVUS-guided PCI group (5.3% vs 4.7%, p = 0.903). Image-guided PCI, including IVUS and OCT, is associated with favorable clinical outcomes in patients with AMI at 3 years post-intervention. Additionally, OCT-guided PCI is not inferior to IVUS-guided PCI in patients with AMI. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes mellitus (DM) have a higher prevalence of heart failure (HF) than those without it. Approximately 40 % of HF patients have DM and they tend to have poorer outcomes than those without DM. This study evaluated the impact of insulin therapy on mortality among acute HF patients. Methods: A total of 1740 patients from the Korean Acute Heart Failure registry with DM were included in this study. The risk of all-cause mortality according to insulin therapy was assessed using the Cox proportional hazard models with inverse probability of treatment weighting to balance the clinical characteristics (pretreatment covariates) between the groups. Results: DM patients had been treated with either oral hypoglycemic agents (OHAs) alone (n = 620), insulin alone (n = 682), or insulin combined with OHAs (n = 438). The insulin alone group was associated with an increased mortality risk compared with the OHA alone group (HR = 1.41, 95 % CI 1.21–1.66]). Insulin therapy combined with OHAs also showed an increased mortality risk (HR = 1.29, 95 % CI 1.14–1.46) compared with the OHA alone group. Insulin therapy was consistently associated with increased mortality risk, regardless of the left ventricular ejection fraction (LVEF) or HF etiology. A significant increase in mortality was observed in patients with good glycemic control (HbA1c < 7.0 %) receiving insulin, whereas there was no significant association in patients with poor glycemic control (HbA1c ≥ 7.0%). Conclusions: Insulin therapy was found to be associated with increased mortality compared to OHAs. The insulin therapy was harmful especially in patients with low HbA1c levels which may suggest the necessity of specific management strategies and blood sugar targets when using insulin in patients with HF. [ABSTRACT FROM AUTHOR]

The authors performed this study to investigate the efficacy and safety of a rosuvastatin (RSV)/amlodipine (AML) polypill compared with those of atorvastatin (ATV)/AML polypill. We included 259 patients from 21 institutions in Korea. Patients were randomly assigned to 1 of 3 treatment groups: RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, or ATV 20 mg /AML 5 mg. The primary endpoint was the efficacy of the RSV 10.20 mg/AML 5 mg via percentage changes in LDL‐C after 8 weeks of treatment, compared with the ATV 20 mg /AML 5 mg. There was a significant difference in the mean percentage change of LDL‐C at 8 weeks between the RSV 10 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (full analysis set [FAS]: −7.08%, 95% CI: −11.79 to −2.38, p =.0034, per‐protocol analysis set [PPS]: −6.97%, 95% CI: −11.76 to −2.19, p =.0046). Also, there was a significant difference in the mean percentage change of LDL‐C at 8 weeks between the RSV 20 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (FAS: −10.13%, 95% CI: −15.41 to −4.84, p =.0002, PPS: −10.96%, 95% CI: −15.98 to −5.93, p <.0001). There was no significant difference in the adverse events rates between RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, and ATV 20 mg/AML 5 mg. In conclusion, while maintaining safety, RSV 10 mg/AML 5 mg and the RSV 20 mg/AML 5 mg more effectively reduced LDL‐C compared with the ATV 20 mg /AML 5 mg (Clinical trial: NCT03951207). [ABSTRACT FROM AUTHOR]

We investigated if elevated cardiac troponin I (cTnI) serum levels before non-cardiac surgery were predictors of postoperative cardiac events in patients with end stage renal disease (ESRD) undergoing dialysis. In total, 703 consecutive patients with ESRD undergoing dialysis who underwent non-cardiac surgery were enrolled. Preoperative cTnI serum levels were measured at least once in all patients. The primary endpoint was defined as a composite of cardiac death, myocardial infarction (MI), and pulmonary edema during hospitalization or within 30 days after surgery in patients with a hospitalization longer than 30 days after surgery. Postoperative cardiac events occurred in 48 (6.8%) out of 703 patients (cardiac death 1, MI 18, and pulmonary edema 33). Diabetes mellitus (DM), previous ischemic heart disease, and congestive heart failure were more common in patients with postoperative cardiac events. Peak cTnI serum levels were higher in patients with postoperative cardiac event (180 ± 420 ng/L vs. 80 ± 190 ng/L, p = 0.008), and also elevated peak cTnI levels > 45 ng/L were more common in patients with postoperative cardiac events (66.8% vs. 30.5%, p < 0.001). Multivariate logistic regression analysis showed that DM (odds ratio [OR] 2.509, 95% confidence interval [CI] 1.178–5.345, p = 0.017) and serum peak cTnI levels ≥ 45 ng/L (OR 3.167, 95% CI 1.557–6.444, p = 0.001) were independent predictors for the primary outcome of cardiac death/MI/pulmonary edema. Moreover, cTnI levels ≥ 45 ng/L had an incremental prognostic value to the revised cardiac risk index (RCRI) (Chi-square = 23, p < 0.001), and to the combined RCRI and left ventricular ejection fraction (Chi-square = 12, p = 0.001). Elevated preoperative cTnI levels are predictors of postoperative cardiac events including cardiac death, MI, and pulmonary edema in patients with ESRD undergoing non-cardiac surgery. [ABSTRACT FROM AUTHOR]

There is insufficient information on the relationship between the N-terminal pro-brain natriuretic peptide (NT-proBNP) level and collateral circulation (CC) formation after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction. We analyzed 857 patients who underwent primary PCI. The serum NT-proBNP levels were measured on the day of admission, and the CC was scored according to Rentrop's classification. Log-transformed NT-proBNP levels were significantly higher in patients with good CC compared to those with poor CC (6.13 ± 2.01 pg/mL versus 5.48 ± 1.97 pg/mL, p < 0.001). The optimum cutoff value of log NT-proBNP for predicting CC was 6.04 pg/mL. Log NT-proBNP ≥ 6.04 pg/mL (odds ratio 2.23; 95% confidence interval 1.51–3.30; p < 0.001) was an independent predictor of good CC. CC development was higher in patients with a pre-TIMI flow of 0 or 1 than those with a pre-TIMI flow of 2 or 3 (22.6% versus 8.8%, p = 0.001). The incidence of left ventricular (LV) dysfunction (< 50%) was greater in patients with a pre-TIMI flow of 0 or 1 (49.8% versus 35.5%, p < 0.001). The release of NT-proBNP was greater in patients with LV dysfunction (34.3% versus 15.6%, p < 0.001). The incidence of good CC was greater in patients with log NT-proBNP levels ≥ 6.04 pg/ml (16.8% versus 26.2%, p = 0.003). The association between NT-proBNP and collateral formation was not influenced by pre-TIMI flow and LV function. NT-proBNP appears to reflect the degree of collateral formation in the early phase of STEMI and might have a new role as a useful surrogate biomarker for collateral formation in patients undergoing primary PCI. [ABSTRACT FROM AUTHOR]

We developed and assessed whether a novel neutrophil-to-hemoglobin and lymphocyte (NHL) score would improve the ability to predict clinical outcome compared with neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) in acute myocardial infarction (AMI). We examined 13,072 AMI patients from the Korean AMI Registry–National Institute of Health database. NHL score was calculated as follows: NHL score (U) = N/(Hb × L), where N, Hb, and L are baseline blood neutrophil, hemoglobin, and lymphocyte count. The primary outcome was the occurrence of major adverse cerebrocardiovascular events (MACCEs) at 2 years. The NLR, SII, and NHL score were independent predictors of 2-year MACCEs. The area under the curve of the NHL score (0.637) for predicting 2-year MACCEs was significantly higher compared with those of SII (0.589) and NLR (0.607). The NHL score significantly improved the reclassification and integrated discrimination compared with NLR (p < 0.0001) and SII (p < 0.0001). A high NHL score (≥ 0.35 U) was an independent predictor of 2-year MACCEs (adjusted hazard ratio, 1.41; 95% confidence interval, 1.29–1.55; p < 0.001). The NHL score could be a novel model for predicting long-term MACCEs in patients with AMI. [ABSTRACT FROM AUTHOR]

Variations by hospital and region in the selection of an early invasive strategy (EIS) after non–ST-segment elevation myocardial infarction (NSTEMI) in patients with high-risk criteria are unknown. We evaluated the data of 7037 patients with NSTEMI from 20 hospitals of 3 regions from the Korean Acute Myocardial Infarction Registry–National Institute of Health database. We used hierarchical generalized linear mixed-models to estimate region- and hospital-level variation in the selection of an EIS after adjusting for patient-level high-risk criteria. We explored the variation using the median rate ratio (MRR), which estimates the relative difference in the risk ratios of two hypothetically identical patients at two different sites. An EIS was selected in 84.4% of patients. At the hospital level, the median selection rate was 80.4%. At the region level, the median selection rate was 74.9% in the east region, 81.3% in the north region, and 83.9% in the west region, respectively. After adjusting for patient-level covariates, we found significant hospital- (MRR 2.19, 95% confidence interval [CI]: 1.74–3.03) and region-level (MRR 1.88, 95%CI: 1.26–5.44) variation in the selection of an EIS. Among patient-level factors, male sex, ongoing chest pain, history of coronary artery disease or acute heart failure, and GRACE risk score > 140 were independently associated with the selection of an EIS. We observed significant hospital- and region-level variation in the selection of an EIS after NSTEMI in high-risk patients. Quality improvement efforts are required to standardize decision making and to improve clinical outcomes. • There is significant hospital- and region-level variation in early invasive strategy selection. • An early conservative strategy is often chosen when an early invasive strategy would provide more benefit. • Site-level variation reflects that there is significant undertreatment for high-risk patients that could worsen clinical outcome. • Quality improvement efforts are required to standardize decision making and improve clinical outcomes. [ABSTRACT FROM AUTHOR]

This study sought to determine hospital variation in the use of follow-up stress testing (FUST) and invasive coronary angiography (FUCAG) after percutaneous coronary intervention (PCI). The claims records of 150,580 Korean patients who received PCI in 128 hospitals between 2008 and 2015 were analyzed. Patient were considered to have undergone FUST and FUCAG, when these testings were performed within two years after discharge from the index hospitalization. Hierarchical generalized linear and frailty models were used to evaluate binary and time-to-event outcomes. Hospital-level risk-standardized FUCAG and FUST rates were highly variable across the hospitals (median, 0.41; interquartile range [IQR], 0.27–0.59; median, 0.22; IQR, 0.08–0.39, respectively). The performances of various models predicting the likelihood of FUCAG and FUST were compared, and the best performance was observed with the models adjusted for patient case mix and individual hospital effects as random effects (receiver operating characteristic curves, 0.72 for FUCAG; 0.82 for FUST). The intraclass correlation coefficients of the models (0.41 and 0.68, respectively) indicated that a considerable proportion of the observed variation was related to individual institutional effects. Higher hospital-level FUCAG and FUST rates were not preventive of death or myocardial infarction. Increased repeat revascularizations were observed in hospitals with higher FUCAG rates. [ABSTRACT FROM AUTHOR]

We developed and assessed whether a novel neutrophil-to-hemoglobin and lymphocyte (NHL) score would improve the ability to predict clinical outcome compared with neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) in acute myocardial infarction (AMI). We examined 13,072 AMI patients from the Korean AMI Registry–National Institute of Health database. NHL score was calculated as follows: NHL score (U) = N/(Hb × L), where N, Hb, and L are baseline blood neutrophil, hemoglobin, and lymphocyte count. The primary outcome was the occurrence of major adverse cerebrocardiovascular events (MACCEs) at 2 years. The NLR, SII, and NHL score were independent predictors of 2-year MACCEs. The area under the curve of the NHL score (0.637) for predicting 2-year MACCEs was significantly higher compared with those of SII (0.589) and NLR (0.607). The NHL score significantly improved the reclassification and integrated discrimination compared with NLR (p < 0.0001) and SII (p < 0.0001). A high NHL score (≥ 0.35 U) was an independent predictor of 2-year MACCEs (adjusted hazard ratio, 1.41; 95% confidence interval, 1.29–1.55; p < 0.001). The NHL score could be a novel model for predicting long-term MACCEs in patients with AMI. [ABSTRACT FROM AUTHOR]

Background: This study investigates the impact of the occurrence of Osborn waves during therapeutic hypothermia (TH) on the recurrence of future fatal arrhythmias in patients resuscitated after sudden cardiac arrest (SCA). Methods: Of all survivors of out‐of‐hospital SCA, 100 consecutive patients (mean age, 52 ± 15 years; 80% men) who received TH were included in this study. Results: The most common first documented arrhythmia was ventricular fibrillation (VF) (77%), and ischemic heart disease (44%) and idiopathic VF (22%) were the most common causes of SCA in resuscitated patients. During TH, Osborn waves developed in 29 patients (29%). Osborn waves occurred more frequently in patients with Brugada syndrome. Patients with Osborn waves had lower in‐hospital (10.3% vs 26.8%; P =.072) and 1‐year death rates (20.7% vs 39.4%; P =.073) and better cerebral function (cerebral performance category scale, 2.0 ± 1.5 vs 2.7 ± 1.8; P =.053) than those without Osborn waves, although there was no statistical significance. Among 78 in‐hospital survivors, 31 (40%) underwent implantable cardioverter‐defibrillator (ICD) implantation. Appropriate ICD shocks from fatal arrhythmias were more frequent in patients who had Osborn waves than in those without Osborn waves (43% vs 6%; P =.032). Conclusions: Osborn waves during TH had no significant effect on the survival and cerebral function of patients resuscitated SCA. However, appropriate ICD shocks due to the recurrence of VF were more frequent in patients with Osborn waves during long‐term follow‐up. [ABSTRACT FROM AUTHOR]

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a life-threatening autosomal dominant disease caused by the deposition of amyloid fibrils composed of TTR proteins. Symptoms of this disease include progressive sensorimotor neuropathy, cardiomyopathy, and involvement of other organs. We described a pediatric case of extremely early onset TTR-FAP with a TTR Leu55Pro mutation. A 17-year-old boy began to suffer from lower limb weakness, gait disturbance, and decreased sensation from 14 years of age onward. He presented with hypertrophic cardiomyopathy, periorbital and scleral ecchymosis, anhidrosis, orthostatic intolerance, and gastrointestinal autonomic dysfunction including nausea, vomiting, and diarrhea alternating with constipation. The patient's older sister had developed similar gastrointestinal symptoms from 20 years of age onward and was diagnosed as having hypertrophic cardiomyopathy. The boy's biopsy results showed infiltrated amyloid deposition on subcutaneous fat tissue and endocardium. Genetic analysis of the TTR gene demonstrated that both the patient and his sister had a pathogenic mutation, c.224T > C (Leu55Pro). Both patients were prescribed tafamidis, a TTR stabilizing agent. Although a majority of TTR-FAPs occur during adulthood, it should be suspected, even in pediatric populations, when symmetric length dependent neuropathy occurs in conjunction with a family history of neuropathy, autonomic neuropathy, and/or cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background Left cardiac sympathetic denervation (LCSD) has been underutilized in patients with hereditary ventricular arrhythmia syndromes such as congenital long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The purpose of this study was to investigate the safety and efficacy of video-assisted thoracoscopic (VATS) LCSD in such patients. Methods Fifteen patients (four men, 24.6 ± 10.5 years old) who underwent VATS-LCSD between November 2010 and January 2015 for hereditary ventricular arrhythmia syndromes at Kyungpook National University Hospital were enrolled in this study. The safety and efficacy of VATS-LCSD were evaluated by periprocedural epinephrine tests and assessing the development of complications and cardiac events during follow-up. Results Fourteen patients with LQTS and one patient with CPVT underwent VATS-LCSD. Six and one patients developed ventricular tachyarrhythmia during preprocedural and postprocedural epinephrine test, respectively (P = 0.063). No serious complications such as Horner syndrome, pneumothorax, or bleeding developed after LCSD. Mean hospital stay after VATS-LCSD was 3.7 ± 1.5 days. During a mean follow-up of 927 ± 350 days, one LQTS patient and one CPVT patient, neither of whom manifested tachyarrhythmia during post-LCSD epinephrine test, developed torsades de pointes and syncope, respectively. The annual event rates of six patients who were symptomatic during the period preceding LCSD decreased from 0.97 to 0.19 events/year (P = 0.045). Conclusions VATS-LCSD was a safe, and effective procedure for patients with hereditary ventricular tachycardia syndrome, with no serious adverse events and with short hospital stay. [ABSTRACT FROM AUTHOR]

Dyslipidemia is a major risk factor for development of atherosclerosis and cardiovascular disease (CVD). Effective lipid-lowering therapies has led to CVD risk reduction. This study evaluated the possible pharmacokinetic interactions between fenofibrate, a peroxisome proliferators-activated receptors α agonist, and pitavastatin, a 3-hydoxy-3-methylglutaryl-coenzyme A reductase inhibitor, in healthy Korean subjects. The study design was an open-label, randomized, multiple-dose, three-period, and six-sequence crossover study with a 10-day washout in 24 healthy volunteers. It had three treatments: 160 mg of micronized fenofibrate once daily for 5 days; 2 mg of pitavastatin once daily for 5 days; and 160 mg of micronized fenofibrate with 2 mg of pitavastatin for 5 days. Serial blood samples were collected at scheduled intervals for up to 48 h after the last dose in each period to determine the steady-state pharmacokinetics of both drugs. Plasma concentrations of fenofibric acid and pitavastatin were measured using a validated high-performance liquid chromatography with the tandem mass spectrometry method. A total of 24 subjects completed the study. Pitavastatin, when co-administered with micronized fenofibrate, had no effect on the Cmax,ss and AUCτ,ss of fenofibric acid. The Cmax,ss and AUCτ,ss of pitavastatin were increased by 36% and 12%, respectively, when co-administered with fenofibrate. Combined treatment with pitavastatin and micronized fenofibrate was generally well tolerated without serious adverse events. Our results demonstrated no clinically significant pharmacokinetic interactions between micronized fenofibrate and pitavastatin when 160 mg of micronized fenofibrate and 2 mg of pitavastatin are co-administered. The treatments were well tolerated during the study, with no serious adverse events. [ABSTRACT FROM AUTHOR]