Distinguishing the impact of dexlansoprazole on heartburn vs. regurgitation in patients with gastro-oesophageal reflux disease.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is characterised by symptomatic heartburn and regurgitation. Treatment with proton pump inhibitors (PPI) effectively decreases heartburn symptoms, but their effects on symptomatic regurgitation are less clear. AIM: To determine the impact of PPI therapy on heartburn and regurgitation severity in patients with either non-erosive GERD (NERD) or erosive oesophagitis (EE). METHODS: Endoscopically-confirmed NERD patients received dexlansoprazole 30 or 60 mg or placebo in a randomised, blinded, 4-week study. Endoscopically-confirmed EE patients received dexlansoprazole 60 mg or lansoprazole 30 mg in two 8-week, randomised, blinded healing studies. The Patient Assessment of Upper Gastrointestinal Symptom Severity questionnaire, which includes a heartburn/regurgitation subscale, was administered to assess symptom severity at baseline, and at weeks 2 and 4 of the NERD study and at weeks 4 and 8 during the EE trials. We defined separate subscales for heartburn and regurgitation for this post-hoc analysis. Among patients with both symptoms at baseline, improvements in individual heartburn and regurgitation subscales along with the original combined heartburn/regurgitation subscale were determined. RESULTS: In the NERD and EE studies, 661 and 1909 patients, respectively, had both heartburn and regurgitation at baseline. NERD patients receiving dexlansoprazole 30 and 60 mg experienced significantly greater improvements in symptom severity for both heartburn and regurgitation compared with placebo. EE patients receiving dexlansoprazole 60 mg had significantly greater improvements in heartburn/regurgitation and heartburn-only subscales at week 4 compared with those receiving lansoprazole. CONCLUSIONS: Dexlansoprazole appears to be effective in improving both heartburn and regurgitation, and this improvement is maintained for the duration of treatment.

The effects of increasing body mass index on heartburn severity, frequency and response to treatment with dexlansoprazole or lansoprazole.

BACKGROUND: Higher body mass index (BMI) is a recognised risk factor for gastro-oesophageal reflux disease (GERD). Data regarding the impact of BMI on proton pump inhibitor (PPI) therapy are conflicting. AIM: To assess the impact of BMI on baseline heartburn symptom severity and frequency and response to PPI therapy in patients with non-erosive GERD (NERD) or erosive oesophagitis (EO). METHODS: In post hoc analyses of phase 3 trial data, 621 NERD and 2692 EO patients were stratified by BMI (<25, 25 to <30 and ≥30 kg/m(2) ). NERD patients received either dexlansoprazole MR 30 mg or placebo daily for 4 weeks. EO patients received either dexlansoprazole MR 60 mg or lansoprazole 30 mg for 8 weeks. Symptom frequency and severity were assessed at baseline and subsequently by daily diary. RESULTS: In both the NERD and EO cohorts, baseline heartburn severity increased with increasing BMI. The impact of PPI therapy on the reduction in heartburn symptom frequency and severity in both NERD and EO patients was similar across BMI categories. EO healing rates in patients treated with dexlansoprazole but not lansoprazole were higher in obese patients compared with those with a BMI <30 kg/m(2) . Differences between the PPIs were small. CONCLUSIONS: The PPIs evaluated in this study reduced the frequency and severity of 24-h heartburn regardless of baseline BMI. In addition, because patients with higher BMI have more severe symptoms at baseline, they may experience greater therapeutic gain with dexlansoprazole (NERD and erosive oesophagitis) and possibly lansoprazole (erosive oesophagitis) treatment.

Risk factors associated with a decrease ≥2 g/dL in haemoglobin and/or ≥10% haematocrit in osteoarthritis patients taking celecoxib or a nonselective NSAID plus a PPI in a large randomised controlled trial (CONDOR).

BACKGROUND: Nonsteroidal anti-inflammatory drugs are associated with gastrointestinal (GI) damage. The Celecoxib vs. Omeprazole and Diclofenac for At-Risk Osteoarthritis and Rheumatoid Arthritis Patients (CONDOR) trial showed that a haemoglobin drop ≥2 g/dL adjudicated as either of defined or presumed GI origin was the most frequent component/event for the composite GI primary end point. This adverse event is potentially clinically relevant in long-term NSAID treatment. AIM: To define potential risk factors associated with a decrease in haemoglobin/haematocrit. METHODS: Post hoc analysis of the CONDOR trial was conducted in the intention-to-treat population. Clinically significant blood loss was defined as: (i) a haemoglobin drop ≥2 g/dL and/or a haematocrit drop ≥10%; and (ii) blood loss adjudicated as either of defined or presumed GI origin. Fifteen risk factors were evaluated by stepwise logistic regression. Each factor had to be significant at <0.20 α to be included in the model. RESULTS: A total of 64/3774 (1.7%) osteoarthritis (OA) patients had decreased haemoglobin/haematocrit and were adjudicated to the GI endpoint. Significant risk factors, at the 0.20 α level found to be associated with clinically significant blood loss in OA patients included [odds ratio (80% CI)] baseline C-reactive protein (CRP) levels [2.27 (1.46-3.53)], history of gastritis and history of GI intolerance [1.55 (1.06-2.28)], positive Helicobacter pylori at screening [1.54 (1.07-2.22)], increasing age [1.17 (1.04-1.32)] and body mass index [BMI; 1.03 (1.00-1.06)]. CONCLUSIONS: Monitoring for decreases in haemoglobin should be considered for all OA patients and especially those with an increased age, BMI, history of gastritis and GI intolerance, CRP levels >1 mg/dL and/or positive H. pylori status, as this may affect their clinical management.

The 12-month safety profile of dexlansoprazole, a proton pump inhibitor with a dual delayed release formulation, in patients with gastro-oesophageal reflux disease.

BACKGROUND: Dexlansoprazole MR is a Dual Delayed Release formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to extend the duration of acid suppression. AIM: To assess the 12-month safety of dexlansoprazole MR in patients with symptomatic gastro-oesophageal reflux disease (GERD). METHODS: In this randomised open-label study, patients received dexlansoprazole MR 60 or 90 mg once-daily for 12 months. Safety was evaluated at months 1, 3, 6, 9 and 12/final visit through physical examinations, laboratory evaluations, endoscopies, gastric biopsies, fasting serum gastrin values and adverse events (AEs). RESULTS: Of 591 patients receiving dexlansoprazole MR 60 and 90 mg, 71% and 65%, respectively, experienced ≥1 treatment-emergent AE; the most frequent AE was upper respiratory infection (14% and 13% in the 60- and 90-mg groups). Thirty patients experienced ≥1 serious AE; a majority of serious AEs were unrelated to study drug. No clinically meaningful change in any clinical laboratory parameters was noted. As expected, serum gastrin values rose with dexlansoprazole therapy; increases were not dose related. No clinically concerning trends were identified in gastric pathology results; no endocrine cell hyperplasia, adenocarcinoma, or lymphoma were observed. CONCLUSIONS: Twelve-month treatment with dexlansoprazole MR 60 and 90 mg was well tolerated by GERD patients in this study (Clinicaltrials.gov identifier NCT00255190).

Changes of gastric histology in patients with erosive oesophagitis receiving long-term lansoprazole maintenance therapy.

BACKGROUND: Changes in gastric histology associated with long-term maintenance therapy with lansoprazole for erosive oesophagitis have not been well described. AIM: To evaluate the effect on gastric histology of long-term dose-titrated lansoprazole administered as maintenance therapy for up to 82 months in patients with erosive oesophagitis. METHODS: Sequential gastric biopsy specimens were obtained for evaluation of histological changes and Helicobacter pylori infection status. RESULTS: Active and chronic inflammation improved from baseline to final visit in a majority of patients receiving long-term therapy with lansoprazole, irrespective of baseline H. pylori infection status. Reductions in active inflammation in the gastric body and antrum were seen in 53% (17/32) and 67% (20/30) of H. pylori-positive patients, respectively, and in 88% (7/8) and 86% (12/14) of H. pylori-negative patients, respectively. Reductions in chronic inflammation in the gastric body and antrum were seen in 38% (12/32) and 47% (15/32) of H. pylori-positive patients, respectively, and in 58% (70/121) and 57% (68/120) of H. pylori-negative patients, respectively. No clinically meaningful increases in hyperplasia, dysplasia, neoplasia, intestinal metaplasia or atrophy were observed during the follow-up period. CONCLUSIONS: Lansoprazole administered as maintenance therapy for up to 6 years in patients with erosive oesophagitis demonstrated gastric mucosal safety and was well tolerated.

Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience.

BACKGROUND: Dexlansoprazole MR is a dual delayed release formulation of dexlansoprazole, an enantiomer of lansoprazole. AIM: To assess safety of dexlansoprazole MR in phase 3 clinical trials. METHODS: Data from 4270 patients receiving dexlansoprazole MR 30 mg (n = 455), 60 mg (n = 2311) or 90 mg (n = 1864); lansoprazole 30 mg (n = 1363); or placebo (n = 896) in six randomized controlled trials and a 12-month safety study were pooled. Safety was assessed via adverse events, vital signs, electrocardiograms, clinical laboratory results and gastric biopsies. Adverse events were summarized per 100 patient-months of exposure to account for imbalances in study drug exposure. RESULTS: The number of patients with > or =1 treatment-emergent adverse event per 100 patient-months was higher in placebo (24.49) and lansoprazole (21.06) groups than in any dexlansoprazole MR (15.64-18.75) group. Fewer patients receiving dexlansoprazole MR discontinued therapy because of an adverse event (P < or = 0.05 vs. placebo). Seven patients died of events considered unrelated to study drug. Mean serum gastrin rose in all groups except placebo; increases were not dose-related. No clinically concerning trends were seen in gastric biopsy results. Endocrine cell hyperplasia, dysplasia and neoplasia were not observed. CONCLUSION: Dexlansoprazole MR 30-90 mg has a safety profile comparable to that of lansoprazole.

Clinical trial: lansoprazole 15 or 30 mg once daily vs. placebo for treatment of frequent nighttime heartburn in self-treating subjects.

BACKGROUND: Frequent nighttime heartburn is common. Lansoprazole 15 mg is indicated for treatment of heartburn and other gastro-oesophageal reflux disease-related symptoms. AIM: To evaluate the efficacy and safety of lansoprazole in self-treating subjects with frequent nocturnal heartburn. METHODS: A total of 864 subjects with heartburn on >or=2 days/week over the past month were randomized to double-blind treatment with lansoprazole 15 or 30 mg or placebo each morning. Endpoints were percentage of night times without heartburn (primary), percentage of 24-h days without heartburn and percentage of subjects without heartburn on day 1. RESULTS: Mean percentage of night times without heartburn was significantly greater with lansoprazole 15 mg (61.3%) or lansoprazole 30 mg (61.7%) vs. placebo (47.8%) over 14 days (P < 0.0001 vs. placebo for both doses). Percentage of 24-h days without heartburn and percentage of subjects without heartburn on day 1 were significantly greater with lansoprazole 15 or 30 mg vs. placebo. CONCLUSIONS: Both lansoprazole 15 and 30 mg were highly effective and well tolerated in reducing symptoms in subjects with frequent nighttime heartburn. The benefit of therapy on 24-h heartburn and nighttime heartburn on day 1 of treatment was also evident. Lansoprazole 15 mg is a suitable choice for management of frequent nighttime heartburn.

The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis.

BACKGROUND: The clinical safety of long-term lansoprazole therapy for the maintenance of healed erosive oesophagitis has not been extensively studied in clinical trials. AIM: To assess the long-term clinical safety of dose-titrated lansoprazole as maintenance therapy for up to 82 months in subjects with healed erosive oesophagitis. METHODS: Clinical safety was assessed by monitoring adverse events (AEs), laboratory data including serum gastrin levels, and endoscopy. RESULTS: Mean duration (+/- s.d.) of lansoprazole treatment during the titrated open-label period was 56 +/- 24 months (range <1-82 months). Overall, 189 of 195 (97%) subjects experienced a total of 2825 treatment-emergent AEs. Most AEs occurred during the first year of treatment, were mild-to-moderate in severity and resolved while on treatment. Of 155 serious AEs (in 74 subjects), only two (colitis and rectal haemorrhage in one subject) were considered treatment-related. Sixty-nine of 195 subjects (35%) experienced 187 treatment-related AEs, with diarrhoea (10%), headache (8%) and abdominal pain (6%) being the most common. Gastrin levels > or = 400 pg/mL were seen in 9% of subjects; hypergastrinemia was not associated with gastro-intestinal AEs or nodules/polyps. CONCLUSIONS: Lansoprazole maintenance therapy for up to 6 years is safe and well tolerated in subjects with healed erosive oesophagitis.

Comparison of Prilosec OTC (omeprazole magnesium 20.6 mg) to placebo for 14 days in the treatment of frequent heartburn.

PURPOSE: Consumer surveys have identified an over-the-counter (OTC) medication that provides complete and long-lasting relief of frequent heartburn as an unmet consumer need. The purpose of the two identical studies reported in this paper was to evaluate the safety and effectiveness of 10.3 and 20.6 mg omeprazole magnesium, referred to as Ome-Mg 10 and Ome-Mg 20, respectively (equivalent to 10 and 20 mg omeprazole) for the treatment of frequent heartburn administered as a novel 14-day OTC regimen. SUBJECTS AND METHODS: Subjects with frequent heartburn (heartburn two or more days per week) took Ome-Mg 10, Ome-Mg 20, or placebo for 14 consecutive mornings. Statistical analyses compared percentage of subjects with no heartburn 24 h after the first dose, after the last dose (day 14), and percentage of days that subjects were heartburn-free. Nocturnal heartburn and heartburn rated no more than mild were also assessed. RESULTS: Twenty-four hours following the first dose, nearly 50% of subjects receiving Ome-Mg 20 reported no heartburn, and more than 80% receiving Ome-Mg 20 had no more than mild heartburn. Both doses were significantly more effective than placebo on days 1 and 14 for percentage of subjects heartburn-free for 24 h (P < or = 0.003), and across all 14 days for percentage of heartburn-free days (P < 0.001). Ome-Mg 20 was significantly more effective than placebo in preventing nocturnal heartburn across all 14 days (P < 0.001). Ome-Mg was well tolerated. CONCLUSION: These trials demonstrated the safety and effectiveness of a novel 14-day regimen of Ome-Mg 20 in completely preventing heartburn for 24 h establishing it as an excellent self-care treatment for frequent heartburn and supporting the approval of Prilosec OTC.

Chairmen's summary: dichotomies and directions in acid-related disorders.

Presentations by international experts from old and new worlds bordering the Atlantic Ocean revealed surprising similarities with respect to the diagnosis and management of patients with upper gastrointestinal disorders. It was agreed that Helicobacter pylori infection continues to play a key role in gastroduodenal disease and has a great impact on clinical management. However, testing and treatment strategies vary in patients affected by functional dyspepsia and those receiving nonsteroidal anti-inflammatory drug (NSAID) therapy including aspirin. Among patients with gastro-oesophageal reflux disease (GERD), it was clear that we need to re-evaluate the validity of the classical concept of GERD as a progressive spectrum and instead focus on the pathophysiologic mechanisms responsible for producing the common symptom of heartburn and complications that occur in the three principle subsets of GERD patients: those with endoscopic negative reflux disease, erosive oesophagitis and Barrett's oesophagus. In addition, we need to be increasingly aware of the concept of extra-oesophageal manifestations of gastro-oesophageal reflux and the fact that GERD in adults often originates in childhood. In all these gastrointestinal disorders, proton pump inhibitor therapy has become the common thread either as a diagnostic tool or an effective short-term or long-term management strategy.

Prevalence of gastric myoelectrical abnormalities in patients with nonulcer dyspepsia and H. pylori infection: resolution after H. pylori eradication.

The aims of this study were to investigate the effects of H. pylori eradication on gastric myoelectrical activity and dyspeptic symptoms. Sixty-two subjects with H. pylori infection and no active peptic ulcer participated in this study, which involved three sessions. Anti-H. pylori therapy consisting of clarithromycin and omeprazole was given for two weeks. Gastric myoelectrical activity was measured using surface electrogastrography and dyspeptic symptoms were scored at each session. A [14C] urea breath test was performed at baseline and one month after treatment. In comparison with baseline, the percentage of normal slow waves was significantly increased and the mean total symptom score was significantly reduced one and three months after therapy (P < 0.05). Approximately 40% of patients with nonulcer dyspepsia' symptoms and H. pylori infection have abnormal gastric myoelectrical activity, which may be normalized following the eradication of H. pylori infection. The normalization of gastric myoelectrical activity may be one explanation for the significant symptom improvement in this subset of the dyspepsia population after H. pylori eradication.

Salivary and gastric epidermal growth factor in patients with Zollinger-Ellison syndrome: its protective potential.

OBJECTIVE: Evidence is accumulating that epidermal growth factor (EGF) is a major molecule contributing to the maintenance of the integrity of the upper alimentary tract mucosa before and after injury by acid and pepsin. Patients with Zollinger-Ellison Syndrome (ZES) typically have hypersecretion of acid and pepsin; however, the concentration and rate of secretion of salivary and gastric EGF that could counteract these potentially aggressive factors are unknown. Accordingly, this study was conducted to determine whether EGF affords mucosal protection in ZES patients. METHODS: The concentration and output of salivary (sEGF) and gastric epidermal growth factor (gEGF) were measured in eight patients with ZES and the results compared to those in 17 patients with nonulcer dyspepsia (NUD), serving as a control group. All patients had normal esophageal and gastric mucosa as determined by endoscopy. Total saliva was collected during 1-h parafilm- and 1-h pentagastrin/parafilm-stimulated conditions, as well as basal and pentagastrin-stimulated gastric juice. The concentration and output of EGF were determined by radioimmunoassay. RESULTS: The concentration of EGF in saliva collected from ZES patients after parafilm chewing was significantly higher compared to that in NUD patients (4.61 +/- 0.59 vs 2.75 +/- 0.50 ng/ml, p < 0.05). The concentration of EGF in saliva collected after pentagastrin stimulation in ZES patients was also significantly higher than in NUD patients (4.37 +/- 0.73 vs 2.22 +/- 0.37 ng/ml, p < 0.05). Salivary EGF output during parafilm chewing in ZES and NUD were similar (68 +/- 6.4 vs 109 +/- 25.2 ng/h). Salivary EGF output after administration of pentagastrin in ZES and NUD was also similar (66 +/- 6.1 vs 132 +/- 45.4 ng/h). Basal EGF output in the gastric juice of patients with ZES was 3-fold higher than in patients with NUD (801 +/- 73 vs 271 +/- 32 ng/h, p < 0.01). Pentagastrin-stimulated EGF output was similar in both groups (705 +/- 92 vs 675 +/- 168 ng/h). CONCLUSIONS: Patients with ZES have a significantly higher EGF concentration in saliva and EGF output in basal gastric juice. This elevated content of salivary and gastric EGF in ZES patients may play a protective role in preventing the development of reflux esophagitis and gastric ulcer under the impact of gastric acid and pepsin hypersecretion.

Helicobacter pylori-related disease: guidelines for testing and treatment.

OBJECTIVE: To develop practical guidelines for the treatment of patients with suspected and documented Helicobacter pylori-related gastroduodenal diseases. METHODS: A panel of physicians with expertise in H. pylori reviewed, critically appraised, and synthesized the literature on assigned topics and presented their overviews to the panel. Consensus was obtained in controversial areas through discussion. RESULTS AND CONCLUSIONS: The panel recommended testing for H. pylori in patients with active ulcers, a history of ulcers, or gastric mucosa-associated lymphoid tissue lymphomas. Young, otherwise healthy patients with ulcerlike dyspepsia and those with a family history or fear of gastric cancer may also undergo H pylori testing. Non-endoscopic methods are preferred for H. pylori diagnosis. Dual medication regimens should not be used for therapy; twice-daily triple therapy with a proton pump inhibitor or ranitidine bismuth citrate, clarithromycin, and amoxicillin for 10 to 14 days is an appropriate therapy. Posttreatment assessment of H. pylori status using urea breath testing should be considered in patients with a documented history of ulcer disease or with persistent symptoms.

The problem of Helicobacter pylori-negative idiopathic ulcer disease.

Ulcer disease is an infectious disease, but for how much longer? Reports of a large number of non-infectious ulcers are becoming more frequent, paralleling the changing prevalence of Helicobacter pylori (H. pylori) in many parts of the world. This chapter will address factors involved in the increasing proportion of H. pylori-negative ulcers, the probable cause of such ulcers and the clinical implications related to their management. This discussion is currently most relevant to those regions of the world where the prevalence of H. pylori is already low or rapidly decreasing. However, it is possible that, even in other areas of the world, the prevalence of infection will also eventually change and H. pylori-negative ulcer disease will become more important.

Usefulness of serological IgG antibody determinations for confirming eradication of Helicobacter pylori infection.

OBJECTIVE: Prior studies have suggested that IgG antibody titers may be useful to confirm successful treatment of Helicobacter pylori (H. pylori) infection. However, the diagnostic value of decreasing IgG titers is limited by the necessity to perform pre and posttreatment tests in parallel which requires stored sera. Our objective was to assess the accuracy of IgG antibody titers using the HM-CAP IgG EIA kit (Enteric Products) in monitoring treatment of H. pylori infection and to compare the relative accuracy of parallel versus serial determinations. METHODS: The 14C urea breath test (UBT) was used to confirm H. pylori infection in 83 dyspeptic patients and eradication of the organism at 4 wk and 6 months posttreatment. IgG titers pretherapy and 6 months posttherapy were determined either serially (separate EIA plates) or in parallel (same EIA plate), and the relative percent decline in antibody titer was calculated. RESULTS: When a decline of > or = 25% at 6 months was used as the cut-off for H. pylori eradication, mean sensitivities of serial and parallel determinations were 87.5% and 86.8%, respectively, and mean specificities of both were 100%. In 68 of 75 patients in whom the organism was eradicated, the mean decrease in IgG titer at 6 months was 41.1% for serial determinations and 41.5% for parallel determinations. CONCLUSIONS: Serial or parallel IgG titers offer equivalent diagnostic accuracy for confirming H. pylori eradication after therapy. A > or = 25% decline in titer 6 months after therapy is a sensitive and specific marker for eradication of the infection. Serial evaluation of IgG titers does not require serum storage, and is a cost-effective and accurate alternative to the UBT or endoscopy-based methods.

Scope and consequences of peptic ulcer disease. How important is asymptomatic Helicobacter pylori infection?

H pylori infection is so common as to seem ubiquitous in many areas of the world. Transmission is believed to be primarily person to person. The pathogen invariably damages the gastric mucosa, resulting in both structural and functional abnormalities. It causes histologic gastritis and is critical in the pathogenesis of the gastritis-associated diseases, namely, gastric ulcer, duodenal ulcer, gastric adenocarcinoma, and primary gastric lymphoma. Elimination of the infection results in healing of gastritis and cure of peptic ulcer disease.

Recognizing peptic ulcer disease. Keys to clinical and laboratory diagnosis.

An algorithmic approach to evaluation of dyspepsia or abdominal discomfort begins with differentiation between peptic ulcer disease and gastroesophageal reflux disease as well as recognition of alarm signs and symptoms for gastric cancer, which are indications for early endoscopy. In the absence of alarm symptoms, most patients should undergo noninvasive testing for H pylori infection with a serologic, urea breath, or stool antigen test. Factors to consider in selection of appropriate testing include reliability, specificity, sensitivity, cost, and local access and expertise. As a general rule, physicians should choose a test that has the best accuracy for the level of testing expertise available. The basic principle underlying testing for H pylori is that patients should not undergo testing unless the physician is willing to treat on the basis of a positive test result. In patients who receive treatment, confirmation of cure is important for preventing further morbidity and reducing risk of transmission of infection.

Practical advice on eradicating Helicobacter pylori infection.

Peptic ulcer disease associated with H pylori infection is curable. The important factors in selecting therapy are efficacy of eradication, prevention of resistance, avoidance or minimization of adverse effects, patient compliance, and cost. The most effective regimens include a bismuth preparation or antisecretory drug (proton pump inhibitor or H2 receptor antagonist) plus two antibiotics administered for 14 days. Dual-drug therapies are not recommended. Triple-drug regimens are more likely to eradicate H pylori and less likely to generate resistant strains among surviving organisms. In general, cure of the infection should be confirmed 4 weeks after completion of the treatment. Antibiotic resistance is an important consideration in choosing therapy, and patients should be taught the importance of compliance. When treatment fails, antibiotic combinations should not be repeated. Considerations for anti-H pylori treatment in a managed care environment mirror those for good medical practice in general, with special attention to stringent cost-control or outcomes-driven measures.