A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.

BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

A scoring system for ascertainment of incident stroke; the Risk Index Score (RISc).

OBJECTIVES: The main objective of this study was to develop and validate a computer-based statistical algorithm that could be translated into a simple scoring system in order to ascertain incident stroke cases using hospital admission medical records data. METHODS: The Risk Index Score (RISc) algorithm was developed using data collected prospectively by the Brain Attack Surveillance in Corpus Christi (BASIC) project, 2000. The validity of RISc was evaluated by estimating the concordance of scoring system stroke ascertainment to stroke ascertainment by physician and/or abstractor review of hospital admission records. RESULTS: RISc was developed on 1718 randomly selected patients (training set) and then statistically validated on an independent sample of 858 patients (validation set). A multivariable logistic model was used to develop RISc and subsequently evaluated by goodness-of-fit and receiver operating characteristic (ROC) analyses. The higher the value of RISc, the higher the patient's risk of potential stroke. The study showed RISc was well calibrated and discriminated those who had potential stroke from those that did not on initial screening. CONCLUSION: In this study we developed and validated a rapid, easy, efficient, and accurate method to ascertain incident stroke cases from routine hospital admission records for epidemiologic investigations. Validation of this scoring system was achieved statistically; however, clinical validation in a community hospital setting is warranted.

Ischemic stroke subtypes among Mexican Americans and non-Hispanic whites: the BASIC Project.

Ischemic stroke subtype distribution was compared between Mexican Americans (MAs) and non-Hispanic whites (NHWs) in a community-based stroke surveillance study in Nueces County, TX. There was no difference in the distribution of stroke subtype by ethnicity (p = 0.19). There was a similar proportion of small-vessel and large-artery strokes between the two ethnic groups (p = 0.32). Differences in stroke rates among MAs and NHWs are not explained by the distribution of ischemic stroke subtypes.

Trials within trials: confirmatory subgroup analyses in controlled clinical experiments.

Subgroup analyses remain a popular and necessary component of controlled clinical trials. However, lack of prospective specification, inadequate sample size, inability to maintain power, and the cumulative effect of sampling error can complicate their interpretation. This article demonstrates that clinical trial design tools that would allow the medical community to draw confirmatory and not just exploratory conclusions from specific subgroup evaluations are available to methodologists. Distinct from the use of a treatment by subgroup interaction term, this methodology provides an evaluation of the effect of an intervention within a particular subgroup stratum prospectively declared to be of interest to the investigators. The necessary prespecification of stratum-specific type I error rates, when combined with (1) a stratum-specific event rate in the subgroup, (2) a stratum-specific primary endpoint, (3) a stratum-specific endpoint precision, and/or (4) a stratum-specific efficacy, satisfies the requirements for a subgroup stratum's "stand-alone" interpretation at the trial's conclusion.

Low-density lipoprotein size, pravastatin treatment, and coronary events.

CONTEXT: Small low-density lipoprotein (LDL) particle size has been hypothesized to be a risk factor for coronary heart disease (CHD). Animal models link large LDL to atherosclerosis. However, the strong association between small LDL and other risk factors, particularly triglyceride levels, impedes determining whether LDL size independently predicts CHD in humans. OBJECTIVE: To examine whether LDL size is an independent predictor of recurrent coronary events in patients with known CHD, as opposed to a marker for other lipid abnormalities. DESIGN AND SETTING: Prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin conducted in 1989-1996. PARTICIPANTS: Survivors of myocardial infarction with typical LDL concentrations (416 cases and 421 controls). MAIN OUTCOME MEASURE: Subsequent myocardial infarction or coronary death during the 5-year follow-up, analyzed by quintile of LDL particle size and by treatment group. RESULTS: Overall, the mean LDL size was identical in cases and controls (25.6 nm). In patients in the placebo group, large LDL predicted coronary events in models adjusted only for age (relative risk [RR], 1.79; 95% confidence interval [CI], 1.01-3.17) and for age and lipid and nonlipid risk factors (RR, 4.00; 95% CI, 1.81-8.82), comparing those in the highest (mean, 26.6 nm) and lowest (mean, 24.5 nm) quintiles of LDL size. This increased risk was not present in those taking pravastatin (age-adjusted analysis: RR, 0.98; 95% CI, 0.47-2.04; P =.046 for interaction for a difference in the effect of LDL size on coronary events between the placebo and treatment groups; multivariable analysis: RR, 1.33; 95% CI, 0.52-3.38; P =.11 for interaction). CONCLUSIONS: Large LDL size was an independent predictor of coronary events in a typical population with myocardial infarction, but the adverse effect was not present among patients who were treated with pravastatin. Identifying patients on the basis of LDL size may not be useful clinically, since effective treatment for elevated LDL cholesterol concentrations also effectively treats risk associated with large LDL.

The platelet Pl(A2) and angiotensin-converting enzyme (ACE) D allele polymorphisms and the risk of recurrent events after acute myocardial infarction.

Chromosome 17q21-23 harbors genes for platelet glycoprotein IIIa and angiotensin-converting enzyme (ACE), which are polymorphic for alleles Pl(A2) and ACE "D." These alleles have been independently and often associated with ischemic coronary artery disease (CAD). We sought to determine if the Pl(A2) and ACE D polymorphisms were risk factors for recurrent coronary events. In the Cholesterol And Recurrent Events (CARE) trial, 4,159 men and women with documented myocardial infarction (MI) were randomized to receive either placebo or pravastatin, and were followed prospectively for 5 years. Pl(A) and ACE genotypes were determined in 767 patients: 385 cases who had experienced a recurrent primary event (death due to coronary disease or nonfatal MI), and 382 age- and gender-matched controls. In patients receiving placebo, the Pl(A1,A2) genotype conferred a relative risk (RR) of 1.38 (confidence intervals [CI] 1.04 to 1.83; p = 0.028; adjusted RR = 1.32, CI = 0.99 to 1.76; p = 0.058]) for the primary end point. Compared with the placebo group, pravastatin reduced the excess RR of coronary disease death and recurrent MI in the Pl(A1,A2) patient population by 31% (p = 0.06). The ACE D allele appeared to have modestly additive effects on the Pl(A1,A2) risk. Among the Pl(A1,A2) patients, pravastatin had little effect on the risk of recurrent events with the ACE II genotype, but reduced the adjusted RR from 1.42 (placebo) to 0.58 for ACE ID patients, and from 1.56 (placebo) to 0.83 for ACE DD. The Pl(A1,A2) genotype was associated with an excess of recurrent coronary events in patients after MI who did not receive pravastatin, and the ACE D allele added to this risk. These data suggest that it would be important to perform a larger study to address the potential role of these genotypes in therapeutic decision making.

Random research.

Advances in computing have combined with the rapid dissemination of treatment discoveries for diseases of public health importance to create pressure for accelerated promulgation of promising research results to the medical community. The 2 recent examples of the US Carvedilol Heart Failure program and the Evaluation of Losartan In the Elderly (ELITE) study demonstrate the importance of the prospective nature of research design, as well as the consequences of its abandonment. This article explains in nonmathematical terms the rationale for the tenet "first say what you will do, then do what you said" in sample-based research.

Barriers to acute stroke therapy and stroke prevention in Mexican Americans.

BACKGROUND AND PURPOSE: The purpose of this study was to identify specific targets to improve acute stroke treatment and stroke prevention in the Mexican American (MA) community. METHODS: A professional, academic survey research team provided structured questions and elicited responses from 719 subjects identified by random-digit dialing in the biethnic community of Corpus Christi, TEXAS: This community of approximately 300 000 is approximately half MA and half non-Hispanic white (NHW). The cooperation rate for the survey was 58%. RESULTS: MAs (n=357) were younger, less well educated, and had lower family income than NHWs (n=362, P=0.001). MAs had a higher prevalence of diabetes mellitus (P=0.001) but similar rates of hypertension, elevated cholesterol, and current tobacco use. MAs less commonly recognized that acute stroke therapy existed (P=0.029), were less likely to acknowledge a time window for acute stroke treatment (P=0.001), and were more reticent to say they would call 911 for stroke symptoms (P=0.01) than NHWS: MAs were significantly less able to recall stroke symptoms and risk factors than NHWS: Only approximately 20% of both groups identified stroke as the NO: 1 cause of disability. MAs expressed less confidence in their ability to prevent stroke (P<0.001), more distrust in the medical establishment (P=0.007), and more concern that money impedes their seeking medical care (P<0.001). CONCLUSIONS: There are significant barriers to both acute stroke treatment and stroke prevention in MAS: This study identifies specific targets amenable for testing in an intervention project following confirmation by a methodology other than telephone survey.

Evaluation of ethnic minorities and gender effects in clinical trials: opportunities lost and rediscovered.

Recent recognition has been given to the notion of demonstrating a beneficial effect of randomly allocated interventions utilized in controlled clinical trials to women and ethnic minorities. However, despite National Institutes of Health (NIH) guidelines on the inclusion of ethnic minorities and women into these studies, clinical trial investigators continue to suffer from an inability to persuasively reach conclusions about the intervention effect in these subgroups. Although a major factor in this limitation has been the inability to recruit large numbers of these patients into controlled clinical trials, an additional dilemma has been the clinical trial community's well demonstrated inability to draw reliable conclusions from the relevant subgroup analyses. As currently designed in clinical trials, subgroup analyses with neither good prospective planning nor concern for the multiplicity of type I error that accompanies the testing of multiple hypotheses are appropriately relegated to exploratory analyses which merely raise questions, not answer them. This article demonstrates that taking advantage of: (a) prospective, subgroup specific endpoint selection; (b) prospective, subgroup specific endpoint event rates; (c) prospective, subgroup specific therapy efficacy, and (d) prospective, subgroup specific nonuniform type I error levels will fortify a subgroup analysis. Thus, the tools traditionally available to clinical trialists, when wielded with renewed vigor and innovation, in concert with energetic, focused recruitment efforts can lead to a confirmatory analysis with appropriate statistical rigor for the effect of the randomly allocated intervention in these important demographic subgroups.

VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial.

BACKGROUND: Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma. METHODS AND RESULTS: We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL-apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P:=0.04), apoCIII in VLDL+LDL (RR 2.3, P:=0.04), and apoE in HDL (RR 1.8, P:=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P:=0.03), was not related to coronary events (RR 1.3, P:=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results. CONCLUSIONS: The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.

Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group.

BACKGROUND: We undertook a prospective systematic overview based on data from individual patients from five long-term randomised trials that assessed inhibitors of angiotensin-converting enzyme (ACE) in patients with left-ventricular dysfunction or heart failure. METHODS: Three of the trials enrolled patients within a week after acute myocardial infarction. Data were combined by use of the Peto-Yusuf method. FINDINGS: Overall 12,763 patients were randomly assigned treatment or placebo and followed up for an average of 35 months. In the three post-infarction trials (n=5,966), mortality was lower with ACE inhibitors than with placebo (702/2995 [23.4%] vs 866/2971 [29.1%]; odds ratio 0.74 [95% CI 0.66-0-83]), as were the rates of readmission for heart failure (355 [11.9%] vs 460 [15.5%]; 0.73 [0.63-0.85]), reinfarction (324 [10.8%] vs 391 [13.2%]; 0.80 [0.69-0.94]), or the composite of these events (1049 [35.0%] vs 1244 [41.9%]; 0.75 [0.67-0.83]; all p

Comparison of stroke hospitalization rates among Mexican-Americans and non-Hispanic whites.

The authors performed a prospective, community-based pilot stroke surveillance project in Nueces County, TX. Mexican-Americans showed a trend toward higher completed ischemic stroke hospitalization rates compared with non-Hispanic whites. Mexican-Americans were more commonly uninsured (p = 0.007) and were less likely to receive neuroimaging (p = 0.001). Additional studies are needed to confirm this finding and to determine the role of stroke risk factors and access to care variables.

Alpha calculus in clinical trials: considerations and commentary for the new millennium.

Regardless of whether a statistician believes in letting a data set speak for itself through nominal p-values or believes in strict alpha conservation, the interpretation of experiments which are negative for the primary endpoint but positive for secondary endpoints is the source of some angst. The purpose of this paper is to apply the notion of prospective alpha allocation in clinical trials to this difficult circumstance. An argument is presented for differentiating between the alpha for the experiment ('experimental alpha' or alpha(E)) and the alpha for the primary endpoint (primary alpha, or alpha(P)) and notation is presented which succinctly describes the findings of a clinical trial in terms of its conclusions. Capping alpha(E) at 0.10 and alpha(P) at 0.05 conserves sample size and preserves consistency with the strength of evidence for the primary endpoint of clinical trials. In addition, a case is presented for the well defined circumstances in which a trial which did not reject the null hypothesis for the primary endpoint but does reject the null hypothesis for at least one of the secondary endpoints may be considered positive in a manner consistent with conservative alpha management.

High-dose-rate brachytherapy for primary carcinomas of the oral cavity and oropharynx.

OBJECTIVE: Local control for patients treated with primary radiation therapy for tumors of the oral cavity is improved using low-dose-rate brachytherapy. Oropharyngeal carcinomas have also been treated with brachytherapy. The few reports in the literature regarding high-dose-rate brachytherapy (HDRBT) for head and neck cancer involve small numbers of patients and often contain a mix of palliative and curative cases. The purpose of this study is to evaluate the feasibility of HDRBT in the largest reported cohort of primary head and neck cancer patients treated with primary radiation therapy. STUDY DESIGN: This is a prospective nonrandomized study. METHODS: Fifty-five patients with primary untreated squamous cell carcinomas of the oral cavity and oropharynx were analyzed. There were 16 patients with T1, 26 with T2, 8 with T3, and 5 with T4 tumors. All patients received external-beam radiotherapy (EBRT) followed by HDRBT. Thirty-eight patients received hyperfractionated (twice daily) EBRT followed by HDRBT two or three times daily. Patients with cervical adenopathy also received hyperthermia and an electron boost to the site(s) of positive nodes. Median follow-up was 2.7 years. Toxicity and local control were analyzed. Data were analyzed by the Kaplan-Meier life-table method with statistical significance determined by the X2 and log-rank tests. RESULTS: High-dose-rate brachytherapy was extremely well tolerated. Only 9 patients (16%) developed a complication. Four patients developed osteoradionecrosis, and five developed soft tissue necrosis, all of which healed with conservative medical management. No complication required surgical intervention or hospitalization. Actuarial 2-year local control for the entire cohort was 79%. Local control was 87% for patients with T1 (15/16) and T2 (22/26) tumors versus 47% for T3 (5/8) and T4 (2/5) tumors (P < .01). CONCLUSIONS: High-dose-rate brachytherapy is feasible as a boost for patients with primary squamous cell carcinomas of the oral cavity and oropharynx. Patients with T1 and T2 tumors fared exceptionally well; those with advanced tumors may require more aggressive treatment, such as higher radiation doses, surgical resection, or systemic chemotherapy. The use of HDRBT both shortens the overall treatment time and limits the volume of tissue exposed to high doses of radiation therapy. In the future, as more patients treated with HDRBT are evaluable, we hope to identify potential factors that predict for local control so that we may select patients optimally for this treatment.

Therapeutic benefit. Aspirin revisited in light of the introduction of clopidogrel.

BACKGROUND: Antiplatelet agents are widely recognized for their efficacy in reducing the occurrence of vascular events in patients with atherothrombotic disease. Aspirin is currently considered to be the "reference standard" antiplatelet agent and is recommended by the American Heart Association for use in patients with a wide range of manifestations of cardiovascular disease on the basis of its high benefit-to-risk and benefit-to-cost ratios. Recently, clopidogrel (Plavix, Bristol-Myers Squibb Co), another antiplatelet agent, was approved by the Food and Drug Administration for many of the same indications as aspirin. SUMMARY OF REVIEW: Because physicians will be faced with deciding whether to switch from the well-established practice of recommending aspirin for use in patients with atherothrombotic disease, both aspirin and clopidogrel are compared with respect to the primary factors that influence such decisions (ie, their relative efficacy, safety, cost, and convenience of use). CONCLUSIONS: Based on the available evidence, aspirin is preferred for the majority of stroke or myocardial infarction patients at risk of recurrent atherothrombotic events. Clopidogrel may, however, provide valuable therapeutic benefit over aspirin in patients with peripheral arterial disease and in stroke or myocardial infarction patients for whom aspirin treatment is contraindicated or for whom aspirin fails to achieve the desired therapeutic effect.

Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators.

OBJECTIVES: This analysis was carried out to determine if revascularized patients derive benefit from the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin. BACKGROUND: The HMG-CoA reductase inhibitors result in substantial reductions in serum cholesterol and stabilization of atherosclerotic plaques in patients with coronary artery disease. METHODS: Pravastatin was found to reduce clinical cardiovascular events in the Cholesterol and Recurrent Events (CARE) trial consisting of 4,159 patients with a documented myocardial infarction and an average cholesterol level (mean 209 mg/dl and all <240 mg/dl). A total of 2,245 patients underwent coronary revascularization before randomization including 1,154 patients with percutaneous transluminal coronary angioplasty (PTCA) alone, 876 patients with coronary artery bypass graft (CABG) alone, and 215 patients with both procedures. Clinical events in revascularized patients were compared between patients on placebo and on pravastatin. RESULTS: In the 2,245 patients who had undergone revascularization, the primary endpoint of coronary heart disease death or nonfatal myocardial infarction (MI) was reduced by 4.1% with pravastatin (relative risk [RR] reduction 36%, 95% confidence interval [CI] 17 to 51, p = 0.001). Fatal or nonfatal MI was reduced by 3.3% (RR reduction 39%, 95% CI 16 to 55, p = 0.002), postrandomization repeat revascularization was reduced by 2.6% (RR reduction 18%, 95% CI 1 to 33, p = 0.068) and stroke was reduced by 1.5% (RR reduction 39%, 95% CI 3 to 62, p = 0.037) with pravastatin. Pravastatin was beneficial in both the 1,154 PTCA patients and in the 1,091 CABG patients who had undergone revascularization before randomization. CONCLUSIONS: Pravastatin reduced clinical events in revascularized postinfarction patients with average cholesterol levels. This therapy was well tolerated and its use should be considered in most patients following coronary revascularization.

Technology evolution: the technology spectrum and its application to orthopedic technologies.

The evolution of clinical technologies presents potential adopters with considerations in planning for clinical program development that include the stage and the rate of a technology's evolution. This paper presents a conceptual framework for these considerations and applies the framework to orthopedic technologies. Eight orthopedic surgeons were asked to assess 14 orthopedic technologies and position each of them along a spectrum of research, clinical, and adopted technologies. The distribution of responses for each technology-year combination is presented, and estimates of central tendency, dispersion, and variances provide measures of the change in the distribution of responses over time for each technology and the change in the degree of rater consensus over time for each technology. While orthopedic trauma was chosen to illustrate the technology spectrum model, the model and assessment methodology is applicable to other medical specialties as well. Adoption of this framework in a hospital setting should enable more systematic and effective clinical program development.