Prespecified Per-protocol Analysis Research Articles

The beneficial effects of adherence to outpatient telecare intervention on clinical outcomes after an episode of acute heart failure: insights from the prospective randomised controlled AMULET trial

Abstract Background The prevention of hospitalisations and deaths is a major therapeutic aim in patients with heart failure (HF). In our previously published prospective randomised controlled trial, we demonstrated that an outpatient intervention comprising nurse-led non-invasive assessments, telemedicine support and remote cardiologist decision-making (AMULET telecare) reduced the risk of HF hospitalisation or cardiovascular death by 31% during the 12-month follow-up in HF patients after an episode of acute HF. Purpose To present the results of the prespecified per-protocol analysis of the AMULET trial that reveal the impact of AMULET telecare adherence on the prognosis of patients. Methods Patients with HF and left ventricular ejection fraction (LVEF) ≤49% and who experienced an episode of acute HF in the past 6 months were randomly assigned to receive either AMULET telecare (n=298) or standard care (n=305). Those who completed the predefined schedule of AMULET telecare (n=190) and all standard care patients were included in the per-protocol population. Results In this per-protocol analysis, when compared to standard care, the implementation of AMULET telecare reduced the risk of the primary outcome, a composite of unplanned HF hospitalisation or cardiovascular death (by 51%), and the following secondary outcomes: first unplanned HF hospitalisation, first unplanned cardiovascular hospitalisation, first all-cause unplanned hospitalisation, total unplanned HF hospitalisations and the number of days lost due to HF hospitalisations or death. There was no statistically significant difference in cardiovascular mortality, mortality due to HF and overall mortality between the study groups (Table). Conclusions Adherence to AMULET telecare enhances the positive effects of this intervention on the prognosis of HF patients with an LVEF≤49% after an episode of acute HF.

Early extracorporeal CPR for refractory out-of-hospital cardiac arrest – A pre-planned per-protocol analysis of the INCEPTION-trial

BackgroundEvidence for extracorporeal cardiopulmonary resuscitation (CPR) in refractory out-of-hospital cardiac arrest (OHCA) remains inconclusive. Recently, the INCEPTION-trial, comparing extracorporeal with conventional CPR, found no statistically significant difference in neurologically favorable survival. Since protocol deviations were anticipated, a pre-specified per-protocol analysis was foreseen. MethodsThe per-protocol analysis of the INCEPTION trial excluded patients not meeting inclusion or exclusion criteria, amongst which time-to-cannulation of >60 minutes, and achieving a return of spontaneous circulation before hospital arrival. Crossovers were excluded as well. The primary outcome (30-day survival in a neurologically favorable condition; cerebral performance category [CPC] 1–2) was primarily analyzed under a frequentist statistical framework. In addition, Bayesian analysis under a minimally informative prior was performed. ResultsEighty-one patients were included in the per-protocol analysis (extracorporeal CPR n = 33, conventional CPR n = 48). Thirty-day survival with CPC1-2 was 15% in the extracorporeal CPR group versus 9% in the conventional CPR group (adjusted OR 1.9; 95% CI 0.4–9.3; p-value 0.393). Bayesian analysis showed an 84% posterior probability of any ECPR benefit and a 61% posterior probability of a 5% absolute risk reduction for the primary outcome. ConclusionA pre-planned, pre-specified per-protocol analysis of the INCEPTION-trial, found a higher survival with favorable neurological in patients undergoing ECPR versus CCPR for refractory shockable OHCA. This difference did not reach statistical significance, but results should be interpreted with care, in the light of the small remaining sample size.

Long-Term Outcome of a Prospective Randomized Trial Comparing Continuous Lenalidomide/Dexamethasone with Lenalidomide/Dexamethasone Induction, MEL140 with Autologous Blood Stem Cell Transplantation and Single Agent Lenalidomide Maintenance in Patients of Age 60-75 Years with Newly Diagnosed Multiple Myeloma

Background: Lenalidomide/dexamethasone has been approved as a standard treatment in multiple myeloma and is applied preferentially in older patients with comorbidities. The addition of daratumumab to this therapy is the best treatment option today for patients who are not transplant eligible. Intensity-reduced high-dose melphalan (MEL140) with autologous transplantation also is an effective treatment option for older patients who are transplant eligible but may not tolerate full dose high-dose melphalan (MEL200). A combination of MEL140 with lenalidomide/dexamethasone potentially could produce a better outcome compared with lenalidomide/dexamethasone alone. Methods: In this trial (DSMM XIII; EudraCT-No: 2008-004083-39) patients of age 60-75 years with newly diagnosed multiple myeloma who had symptomatic and measurable disease were randomly assigned to either (A1) 3 cycles of lenalidomide (25 mg po d1-21/28d) with low-dose dexamethasone (40 mg po d1, d8, d15, d22/28d), followed by stem cell mobilization and then further lenalidomide/dexamethasone cycles until progression or (A2) 3 cycles of lenalidomide/dexamethasone as induction, followed by stem cell mobilization, intensity-reduced high-dose melphalan 140 mg/m2 (MEL140) (single or double) with autologous blood stem cell transplantation and lenalidomide maintenance with 10 mg daily until progression. At randomization, patients were stratified according to age (60-70 years vs 71-75 years) and ISS stage (I, II vs III). The primary endpoint was progression-free survival, and secondary endpoints included safety, response rates and overall survival. Here, we report the long-term outcome. Results: 348 patients were included into the study and 339 patients could be analysed per intention-to-treat (ITT). Patient characteristics were well balanced between treatment arms. For all patients, median age was 68 years (range 60 - 75), 29% were older than 70 years, 36.5% had ISS stage I, 35.6% ISS stage II, and 27.9% ISS stage III. After a median follow-up of 68 months, the median progression-free survival (PFS) was 40 months for A1 (169 patients) and 33 months for A2 (170 patients) (HR 1.16; p=0.19) in the ITT analysis. The median overall survival (OS) was 87 months for A1 and 96 months for A2 (HR 1.04; p=0.81). A prespecified per-protocol (PP) analysis was defined to include patients who received at least 6 months of study treatment (also including patients with progressive disease or death during this time period). In this PP analysis the median PFS was 42 months for A1 (139 patients) and 36 months for A2 (131 patients) (HR 1.15; p=0.27); the median OS was 89 months for A1 and 96 months for A2 (HR 1.01; p=0.96). In arm A2, 115 patients (68%) received one or two transplants. For transplanted patients, median PFS was 40 months and median OS was 114 months. Second primary malignancies (SPMs) were observed in 24 patients in arm A1 (skin 12, solid tumor 11, hematologic 1) and in 20 patients in arm A2 (skin 5, solid tumor 11, hematologic 4). Conclusion: In the intention-to-treat population, the combination of MEL140 with lenalidomide/dexamethasone induction and lenalidomide single agent maintenance was not superior to continuous lenalidomide/dexamethasone treatment. Subgroup analyses with a focus on the role of transplant will be presented at the meeting. Sponsor: Gesellschaft für Medizinische Innovation in der Hämatologie/Onkologie - GMIHO

Ticagrelor monotherapy beyond 1 month versus standard dual antiplatelet therapy after drug-eluting coronary stenting: a pre-specified per-protocol analysis of the GLOBAL LEADERS trial

Abstract Background In the GLOBAL LEADERS trial, the intention-to-treat (ITT) effect of ticagrelor monotherapy after 1 month of dual antiplatelet therapy (DAPT) was not superior to that of 12-month DAPT followed by aspirin alone in the prevention of 2-year all-cause mortality or new Q-wave myocardial infarction (MI) after coronary stenting. Intention-to-treat analyses can be affected by incomplete protocol adherence. We present a pre-specified per-protocol analysis. Purpose To determine whether 1 month of ticagrelor plus aspirin followed by 23 months of ticagrelor monotherapy is superior to 12 months of DAPT followed by aspirin alone in the per-protocol population of the GLOBAL LEADERS (NCT01813435). Methods The GLOBAL LEADERS compared two antiplatelet strategies after drug-eluting stenting for stable coronary artery disease or acute coronary syndromes. Per-protocol population consisted of randomized patients fulfilling enrollment criteria and receiving protocol-mandated treatment. Adherence to the allocated antiplatelet therapy was evaluated at discharge, 30 days, and 3, 6, 12, 18, and 24 months, with non-adherence reasons categorized following a hierarchical approach. A protocol-deviation was defined in the case of high perceived bleeding/thrombotic risk, a medical decision without evident clinical reason, patients unwilling to take study drugs, prescription error, logistical issues, unclear reasons. Baseline characteristics, including (but not limited to) age, sex, diabetes, prior PCI, were used to construct time-varying inverse probabilities for not deviation from the protocol to reconstruct a study population with no protocol-deviations. Protocol deviators were artificially censored at the time at which they deviated. The primary endpoint was the composite of 2-year all-cause mortality or non-fatal new Q-wave MI. We used a weighted pooled logistic regression to estimate the per-protocol rate ratio (RR) of experimental vs. control treatment for the primary endpoint. Results Of the 15,968 randomized patients, 805 out of 7,980 (10.1%) in experimental group and 537 out of 7,988 (6.7%) in control group were classified as protocol deviators and artificially censored by month 12, not contributing events in the second year. The events for the adherence-adjusted analysis were 279 in experimental group and 325 in control group (25 and 24 less than in ITT analysis, respectively). The estimated adherence-adjusted RR was 0.87 (95% CI: 0.74–1.02; p=0.09), comparable to the ITT RR (0.87; 95% CI: 0.75–1.01; p=0.07). Conclusion At per-protocol analysis, ticagrelor monotherapy after 1 month of DAPT was not superior to conventional treatment, in line with the previously reported ITT effect. Similar per-protocol and ITT effects can be accounted for similar per-protocol and ITT populations, as a substantial proportion of patients were non-adherent due to clinically grounded reasons (anticipated in the protocol) and, accordingly, not considered as protocol deviators. Funding Acknowledgement Type of funding source: Other. Main funding source(s): GLOBAL LEADERS was sponsored by the European Clinical Research Institute, which received funding from Biosensors International, AstraZeneca, and the Medicines Company.

Advances in the treatment of biliary tract cancers.

To review new treatment and advances in biliary tract cancer (BTC). In the prespecified per-protocol analysis of the randomized phase III trial BILCAP, adjuvant capecitabine offers overall survival (OS) benefit when compared with observation with statistical significance. In the first-line setting in metastatic BTC, gemcitabine and S-1 had noninferior OS compared with gemcitabine and cisplatin. In a separate phase III study, the triplet of gemcitabine, cisplatin and S-1 (GCS) had superior OS compared with standard gemcitabine and cisplatin. The regimen of modified FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen can be considered a potential standard option in the second-line setting for patients who failed first-line therapy with gemcitabine-based regimens. Trials in genomically selected patients indicate activity of fibroblast growth factor receptor inhibitors, mutant isocitrate dehydrogenase inhibitors and immune checkpoint inhibitors. Capecitabine is a new option for adjuvant treatment in resected BTC. In the metastatic setting, gemcitabine and S-1 or GCS are new options for first-line therapy and modified FOLFOX regimen should be considered as a potential new empirical standard of care in genomically agnostic patients requiring second-line therapy. Future randomized trials will evaluate the role of targeted agents and immunotherapy in advanced BTC, both in monotherapy and in combination.

BEtablocker Treatment After acute Myocardial Infarction in revascularized patients without reduced left ventricular ejection fraction (BETAMI): Rationale and design of a prospective, randomized, open, blinded end point study

Current guidelines on the use of β-blockers in post-acute myocardial infarction (MI) patients without reduced left ventricular ejection fraction (LVEF) are based on studies before the implementation of modern reperfusion and secondary prevention therapies. It remains unknown whether β-blockers will reduce mortality and recurrent MI in contemporary revascularized post-MI patients without reduced LVEF. BETAMI is a prospective, randomized, open, blinded end point multicenter study in 10,000 MI patients designed to test the superiority of oral β-blocker therapy compared to no β-blocker therapy. Patients with LVEF ≥40% following treatment with percutaneous coronary intervention or thrombolysis and/or no clinical signs of heart failure are eligible to participate. The primary end point is a composite of all-cause mortality or recurrent MI obtained from national registries over a mean follow-up period of 3 years. Safety end points include rates of nonfatal MI, all-cause mortality, ventricular arrhythmias, and hospitalizations for heart failure obtained from hospital medical records 30 days after randomization, and from national registries after 6 and 18 months. Key secondary end points include recurrent MI, heart failure, cardiovascular and all-cause mortality, and clinical outcomes linked to β-blocker therapy including drug adherence, adverse effects, cardiovascular risk factors, psychosocial factors, and health economy. Statistical analyses will be conducted according to the intention-to-treat principle. A prespecified per-protocol analysis (patients truly on β-blockers or not) will also be conducted. The results from the BETAMI trial may have the potential of changing current clinical practice for treatment with β-blockers following MI in patients without reduced LVEF. EudraCT number 2018-000590-75.

Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial.

Hand osteoarthritis is a prevalent disease with limited treatment options. Since joint inflammation is often present, we investigated tumour necrosis factor (TNF) as treatment target in patients with proven joint inflammation in a proof-of-concept study. This 1-year, double-blind, randomised, multicentre trial (NTR1192) enrolled patients with symptomatic erosive inflammatory hand osteoarthritis. Patients flaring after non-steroidal anti-inflammatory drug washout were randomised to etanercept (24 weeks 50 mg/week, thereafter 25 mg/week) or placebo. The primary outcome was Visual Analogue Scale (VAS) pain at 24 weeks. Secondary outcomes included clinical and imaging outcomes (radiographs scored using Ghent University Scoring System (GUSS, n=54) and MRIs (n=20)). Of 90 patients randomised to etanercept (n=45) or placebo (n=45), respectively, 12 and 10 discontinued prematurely. More patients on placebo discontinued due to inefficacy (6 vs 3), but fewer due to adverse effects (1 vs 6). The mean between-group difference (MD) in VAS pain was not statistically significantly different (-5.7 (95% CI -15.9 to 4.5), p=0.27 at 24 weeks; - 8.5 (95% CI -18.6 to 1.6), p=0.10 at 1 year; favouring etanercept). In prespecified per-protocol analyses of completers with pain and inflammation at baseline (n=61), MD was -11.8 (95% CI -23.0 to -0.5) (p=0.04) at 1 year. Etanercept-treated joints showed more radiographic remodelling (delta GUSS: MD 2.9 (95% CI 0.5 to 5.4), p=0.02) and less MRI bone marrow lesions (MD -0.22 (95% CI -0.35 to -0.09), p = 0.001); this was more pronounced in joints with baseline inflammation. Anti-TNF did not relieve pain effectively after 24 weeks in erosive osteoarthritis. Small subgroup analyses showed a signal for effects on subchondral bone in actively inflamed joints, but future studies to confirm this are warranted.

Intermittent vs. Continuous Anticoagulation theRapy in patiEnts with Atrial Fibrillation (iCARE-AF): a randomized pilot study.

We hypothesized that intermittent anticoagulation based on daily rhythm monitoring using the novel oral anticoagulants (NOACs) is feasible and safe among patients with paroxysmal atrial fibrillation (AF). Patients with paroxysmal AF and ≥1 risk factors for stroke were randomized to either intermittent or continuous anticoagulation. Those in the intermittent group were instructed to transmit a daily ECG using an iPhone-based rhythm monitoring device. If AF was detected, patients received one of the NOACs for 48h-1week. Patients who failed to transmit an ECG for three consecutive days or more than 7days total were crossed over to continuous anticoagulation. Patients in the continuous group received one of the NOACs. Fifty-eight patients were randomized to either intermittent (n = 29) or continuous anticoagulation (n = 29). Over a median follow-up of 20months, 20 patients in the intermittent group failed to submit a daily ECG at least once (median three failed submissions). Four patients (14%) crossed over to continuous anticoagulation due to failure to submit an ECG for three consecutive days. One stroke (continuous group) occurred during the study. Major bleeding occurred in two patients in the continuous and one patient in the intermittent group, after crossing over to continuous anticoagulation. In a prespecified per-protocol analysis, gastrointestinal bleeding was more frequent in the continuous group (16 vs. 0%; p = 0.047). Intermittent anticoagulation based on daily rhythm monitoring is feasible and may decrease bleeding in low-risk patients with paroxysmal AF. A larger trial, adequately powered to detect clinical outcomes, is warranted.

Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer

GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

Tafamidis: A Review of Its Use in Familial Amyloid Polyneuropathy

Oral tafamidis (Vyndaqel(®)) is indicated in the EU for the treatment of transthyretin (TTR) amyloidosis in adult patients with early stage symptomatic polyneuropathy to delay peripheral neurologic impairment and, in Argentina, Japan and Mexico, for delaying the peripheral neurological impairment of TTR familial amyloid polyneuropathy (TTR-FAP). It is the first disease-modifying pharmacotherapy to be approved for use in adult patients with early-stage TTR-FAP. The drug acts to kinetically stabilize the variant TTR tetramer and thereby prevent tetramer dissociation, the rate-limiting step in TTR misfolding and amyloidogenesis. In the 18-month Fx-005 study in adult patients with early-stage V30M TTR-FAP, there were no statistically significant differences between tafamidis and placebo recipients for the coprimary endpoints, the Neuropathy Impairment Score-Lower Limb (NIS-LL) response rate (increase in NIS-LL score of <2) and the least-square mean change in Norfolk Quality-of-Life (QOL) Diabetic-Neuropathy Questionnaire total scores at 18 months, based on modified intent-to-treat analyses. However, in prespecified per-protocol analyses of efficacy evaluable patients, tafamidis recipients experienced significantly better outcomes in terms of these coprimary endpoints, with most (98%) tafamidis recipients showing stabilization of TTR tetramers at study end. Secondary endpoint outcomes also favoured tafamidis treatment over placebo. The beneficial effects of tafamidis in slowing deterioration of neurological function and health-related-QOL were maintained in long-term extension studies (up to 66 months). Tafamidis also stabilized TTR tetramers in patients with non-V30M TTR-FAP. Tafamidis was generally well tolerated, with most treatment-emergent adverse events being of mild to moderate intensity and very few patients discontinuing treatment because of these events. No new safety signals have emerged during long-term extension studies and post-marketing experience.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial

Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. Canadian Institutes of Health Research.

A Direct Comparison of Intravenous Enoxaparin With Unfractionated Heparin in Primary Percutaneous Coronary Intervention (from the ATOLL Trial)

Intravenous enoxaparin did not reduce significantly the primary end point (p = 0.06) compared with unfractionated heparin (UFH) in the randomized Acute Myocardial Infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up (ATOLL) trial. We present the results of the prespecified per-protocol analysis excluding patients who did not receive the treatment allocated by randomization or received both enoxaparin and UFH. We evaluated all-cause mortality, complication of myocardial infarction, procedural failure, or major bleeding (primary end point) and all-cause mortality, recurrent acute coronary syndrome, or urgent revascularization (main secondary end point). Baseline and procedural characteristics were well balanced between the 2 treatment groups. Of 910 randomized patients, 795 patients (87.4%) were treated according to the protocol with consistent anticoagulation using intravenous enoxaparin (n = 400) or UFH (n = 395). Enoxaparin reduced significantly the rates of the primary end point (relative risk [RR] 0.76, 95% confidence interval [CI] 0.62 to 0.94, p = 0.012) and the main secondary end point (RR 0.37, 95% CI 0.22 to 0.63, p <0.0001). There was less major bleeding with enoxaparin (RR 0.46, 95% CI 0.21 to 1.01, p = 0.050) contributing to the significant improvement of the net clinical benefit (RR 0.46, 95% CI 0.3 to 0.74, p = 0.0002). All-cause mortality was also reduced with enoxaparin (RR 0.36, 95% CI 0.18 to 0.74, p = 0.003). In conclusion, in the per-protocol analysis of the ATOLL trial, pertinent to >87% of the study population, enoxaparin was superior to UFH in reducing ischemic end points and mortality.

Heparin-Induced Thrombocytopenia in Medical Surgical Critical Illness

In a recent multicenter randomized trial comparing unfractionated heparin (UFH) with low-molecular-weight heparin (dalteparin) for thromboprophylaxis in 3,746 critically ill patients, 17 patients (0.5%) developed heparin-induced thrombocytopenia (HIT) based on serotonin-release assay-positive (SRA+) status. A trend to a lower frequency of HIT with dalteparin vs UFH was observed in the intention-to-treat analysis (five vs 12 patients, P = .14), which was statistically significant (three vs 12 patients, P = .046) in a prespecified per-protocol analysis that excluded patients with DVT at study entry. We sought to characterize HIT outcomes and to determine how dalteparin thromboprophylaxis may reduce HIT frequency in patients in the ICU. In 17 patients with HIT, we analyzed platelet counts and thrombotic events in relation to the study drug and other open-label heparin, to determine whether the study drug plausibly explained seroconversion to SRA+ status and/or breakthrough of thrombocytopenia/thrombosis. We also compared antibody frequencies (dalteparin vs UFH) in 409 patients serologically investigated for HIT. HIT-associated thrombosis occurred in 10 of 17 patients (58.8%) (8:1:1 venous:arterial:both). Dalteparin was associated with fewer study drug-attributable HIT-related events (P = .020), including less seroconversion (P = .058) and less breakthrough of thrombocytopenia/thrombosis (P = .032). Antiplatelet factor 4/heparin IgG antibodies by enzyme-linked immunosorbent assay were less frequent among patients receiving dalteparin vs UFH (13.5% vs 27.3%, P &lt; .001). One patient with HIT-associated DVT died after UFH bolus (anaphylactoid reaction), whereas platelet counts recovered in two others with HIT-associated VTE despite continuation of therapeutic-dose UFH. The lower risk of HIT in patients in the ICU receiving dalteparin appears related to both decreased antibody formation and decreased clinical breakthrough of HIT among patients forming antibodies.

Reply to Grey and Bolland: Findings of prespecified per-protocol analysis are valid

We thank Grey et al. for their comments (1). However, contrary to their assertion, our article did not contend that our results provide evidence for treatment efficacy of adjunctive vitamin D in tuberculosis treatment (2). Our finding that sputum smear conversion was accelerated in patients in the per-protocol population who received adjunctive vitamin D is not a “claim” but an observation. We reported it because it places the immunological findings of our study into context. It might well be supposed that suppression …

Dalteparin versus Unfractionated Heparin in Critically Ill Patients

The effects of thromboprophylaxis with low-molecular-weight heparin, as compared with unfractionated heparin, on venous thromboembolism, bleeding, and other outcomes are uncertain in critically ill patients. In this multicenter trial, we tested the superiority of dalteparin over unfractionated heparin by randomly assigning 3764 patients to receive either subcutaneous dalteparin (at a dose of 5000 IU once daily) plus placebo once daily (for parallel-group twice-daily injections) or unfractionated heparin (at a dose of 5000 IU twice daily) while they were in the intensive care unit. The primary outcome, proximal leg deep-vein thrombosis, was diagnosed on compression ultrasonography performed within 2 days after admission, twice weekly, and as clinically indicated. Additional testing for venous thromboembolism was performed as clinically indicated. Data were analyzed according to the intention-to-treat principle. There was no significant between-group difference in the rate of proximal leg deep-vein thrombosis, which occurred in 96 of 1873 patients (5.1%) receiving dalteparin versus 109 of 1873 patients (5.8%) receiving unfractionated heparin (hazard ratio in the dalteparin group, 0.92; 95% confidence interval [CI], 0.68 to 1.23; P=0.57). The proportion of patients with pulmonary emboli was significantly lower with dalteparin (24 patients, 1.3%) than with unfractionated heparin (43 patients, 2.3%) (hazard ratio, 0.51; 95% CI, 0.30 to 0.88; P=0.01). There was no significant between-group difference in the rates of major bleeding (hazard ratio, 1.00; 95% CI, 0.75 to 1.34; P=0.98) or death in the hospital (hazard ratio, 0.92; 95% CI, 0.80 to 1.05; P=0.21). In prespecified per-protocol analyses, the results were similar to those of the main analyses, but fewer patients receiving dalteparin had heparin-induced thrombocytopenia (hazard ratio, 0.27; 95% CI, 0.08 to 0.98; P=0.046). Among critically ill patients, dalteparin was not superior to unfractionated heparin in decreasing the incidence of proximal deep-vein thrombosis. (Funded by the Canadian Institutes of Health Research and others; PROTECT ClinicalTrials.gov number, NCT00182143.).

Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study

The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and North America. Patients with localised high-risk STS (> or = 5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00003052. 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20-67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41-0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6-26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54-0.92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28.8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a pre-specified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45-0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group. To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location. Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).

Immunogenicity of a Tetravalent Meningococcal Glycoconjugate Vaccine in Infants

Immunization with a meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine is recommended for all US adolescents. However, the currently licensed vaccine is poorly immunogenic in infancy, when the highest rates of disease are observed. To determine the immunogenicity of a novel tetravalent CRM(197)-conjugated meningococcal vaccine (MenACWY) in infants. Randomized, open-label, controlled study of 225 UK and 196 Canadian 2-month-olds from August 2004 to September 2006. UK infants received a primary course of MenACWY (at 2, 3, and 4 months or 2 and 4 months) or Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine (MenC) (at 2 and 4 months). All received MenACWY at 12 months. Canadian infants received MenACWY at 2, 4, and 6 months or 2 and 4 months; at 12 months they received MenACWY, a plain tetravalent polysaccharide vaccine, or no vaccine. Percentage of infants with a human complement serum bactericidal activity (hSBA) titer >or=1:4 after a primary course of MenACWY and after a 12-month booster. Safety and reactogenicity of MenACWY were also assessed. According to the prespecified per-protocol analysis, the percentages (95% CIs) of MenACWY 2-, 3-, and 4-month recipients with hSBA titers >or=1:4 after primary immunization were serogroup A, 93% (84%-98%); C, 96% (89%-99%); W-135, 97% (90%-100%); and Y, 94% (86%-98%). With a post hoc intention-to-treat analysis with imputed values for missing data, these values were unchanged for serogroups C and Y; for serogroup A, values were 92% (84%-97%), and for W-135, 97% (91%-99%). For the per-protocol analysis of MenACWY 2-, 4-, and 6-month recipients, the percentages (95% CIs) of responders were A, 81% (71%-89%); C, 98% (92%-100%); W-135, 99% (93%-100%); and Y, 98% (92%-100%). With the imputed value analysis, these values were A, 83% (74%-89%); C, 98% (93%-99%); W-135, 99% (94%-100%); and Y, 98% (92%-99%). At least 84% of MenACWY 2- and 4-month recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y after primary immunization, as did at least 60% for serogroup A (per-protocol and imputation analysis). At least 95% of primary and booster MenACWY recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y at 13 months, as did at least 84% for serogroup A (per-protocol and imputation analysis). During the primary immunization course, postimmunization pain on leg movement was observed in 2% of UK MenACWY 2- and 4-month recipients and 4% of MenC 2- and 4-month recipients; a temperature of 38 degrees C or greater was observed in 4% and 2% in these groups, respectively. MenACWY is well tolerated and immunogenic in infancy. Trial Registration clinicaltrials.gov Identifier: NCT00262002.

Rizatriptan: a review of its efficacy in the management of migraine.

Rizatriptan is an orally active serotonin 5-HT1 receptor agonist selective for the 5-HT(1B/1D) subtypes. The efficacy of oral rizatriptan (5 or 10 mg) has been demonstrated in large (n = 309 to 1746) well designed comparative trials with placebo and oral sumatriptan. Two hours postdose, rizatriptan 5 or 10 mg was more effective than placebo at producing pain relief or a pain free status, relieving migraine-associated symptoms and normalising functional ability. In general, rizatriptan 10 mg appeared to be more effective than rizatriptan 5 mg. However, recurrence rates with rizatriptan 5 and 10 mg appeared to be similar to those with placebo. Patients were significantly more likely to achieve pain relief within 2 hours after receiving rizatriptan 5 mg than sumatriptan 25 mg and after rizatriptan 10 mg than sumatriptan 50 mg. This was also observed with rizatriptan 10 mg compared with sumatriptan 100 mg according to an age-adjusted and a prespecified per-protocol analysis. In general, rizatriptan was better than sumatriptan at relieving migraine-associated symptoms, particularly nausea, and in normalising functional ability depending on which doses were compared. The incidence of headache recurrence, time to onset of recurrence and the need for escape medication in nonresponders appeared to be similar between rizatriptan and sumatriptan. Over the 24 hours after the dose, rizatriptan 10 mg improved the quality of life of patients with migraine compared with placebo. Rizatriptan 10 mg also significantly improved work function compared with placebo and with sumatriptan 50 mg. Rizatriptan appears to be well tolerated with most adverse events being mild and transient. The most commonly experienced events included general digestive complaints, general neurological complaints, dizziness, somnolence, asthenia/fatigue and pain and pressure sensations. In clinical trials, the overall incidence of adverse events with rizatriptan 5 or 10 mg was similar to that with sumatriptan 25 or 50 mg but lower than that with sumatriptan 100 mg. Chest pain was reported by 1 to 3% of rizatriptan recipients and by 3 to 6% of patients receiving sumatriptan (25, 50 or 100 mg); clinically significant effects on ECG parameters, heart rate or blood pressure were not observed with rizatriptan. Rizatriptan produces pain relief and a pain free status, relieves associated symptoms of migraine, normalises functional ability and improves patient quality of life. Rizatriptan 10 mg appears to be more effective than rizatriptan 5 mg. In comparison with oral sumatriptan, rizatriptan may provide better relief from pain and nausea, with some evidence of a faster onset of action. Thus, rizatriptan 5 or 10 mg is likely to establish a place as an effective and well tolerated agent for the management of acute migraine.