The clinical and economic burden of peripheral T-cell lymphoma: a systematic literature review.

Aim: To understand the burden of treatment-naive peripheral T-cell lymphoma (PTCL). Methods: A systematic literature review was conducted in November 2020 following best practice methodology. Results: Fifty-five clinical studies were included, mostly investigating cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or 'CHOP-like' regimens, with combination regimens showing similar effectiveness to CHOP alone. Aside from the combination of brentuximab vedotin + cyclophosphamide, doxorubicin and prednisone (A+CHP), other available treatments showed no statistically significant benefit over CHOP in terms of overall or progression-free survival in overall PTCL patients. The mean monthly cost per patient in the USA ranged from 6328 to US$9356 based on six studies. One economic evaluation demonstrated A+CHP to be a more cost-effective treatment option than CHOP. Conclusion: Further research is needed to understand the humanistic and cost impact of frontline treatment for PTCL and its specific subtypes.

Plain language summary Peripheral T-cell lymphoma (PTCL) is an aggressive cancer that develops from white blood cells called T cells, which are an important part of the immune system. There is limited knowledge on the impact PTCL has on patients and their families. This systematic review of 55 clinical studies was conducted to further understand how safe and effective current treatments are for patients with newly diagnosed PTCL, how these treatments and disease impact their quality of life, and the economic impact of treatment and disease. Chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP]) was the most commonly studied regimen, but had limited effectiveness and a notable side effect profile. A newer treatment option, brentuximab vedotin + cyclophosphamide, doxorubicin and prednisone (A+CHP) was the only treatment to show a significant added benefit over CHOP for patients, with side effects that were comparable to those of CHOP. Six studies assessed the economic impact of PTCL, the majority of which were focused on the USA, and found the mean monthly cost per patient to be 6328­US$9356. No studies were identified that assessed the impact of PTCL or its treatment on quality of life. Further research is needed to understand the impact of frontline PTCL treatment on patients and their families.

Patient preferences for frontline therapies for Philadelphia chromosome-positive acute lymphoblastic leukemia: a discrete choice experiment.

Aim: We examined the preferences of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for benefits and risks of tyrosine kinase inhibitors combined with chemotherapy for first-line treatment. Methods: In a discrete choice experiment, 201 patients chose between hypothetical treatment alternatives with varied levels of remission duration and overall survival (OS), and risks of major cardiovascular (CV) events and myelosuppression. Results: Although OS was the most important attribute to patients with Ph+ ALL, they were willing to tolerate a 2.9% increase in CV risk for 1 additional month of OS. Older patients (>59 years) and patients not in remission were less likely to tolerate increased CV risk. Conclusion: Preferences and risk tolerance varied between patients, highlighting the importance of shared decision making when selecting treatments for Ph+ ALL.

Treatments differ in their potential benefits and side effects they may come with. Patients should be involved in deciding which treatments they receive. This is because patients may have different views than physicians on how the benefits and side effects of treatment would affect their quality of life. Additionally, patients may have different risk tolerances. This study shows how patients with a form of leukemia valued survival benefits and side effects of treatments, and the trade-offs that they were willing to make between these. On average, longer survival had most value to patients. They were willing to accept a higher risk of a major cardiovascular side effect (e.g., having a stroke) if the treatment would allow them to live longer. However, not all patients had the same opinion, and some groups of patients were less willing to accept risks to receive longer survival. By involving patients in treatment decisions, we can help ensure they receive treatments that match their personal preferences.

A comparative evaluation of gemtuzumab ozogamicin + daunorubicin-cytarabine and other treatments for newly diagnosed acute myeloid leukemia.

AIM: To evaluate the comparative efficacy and safety of gemtuzumab ozogamicin + daunorubicin-cytarabine (GO + DA) versus common induction therapies for newly diagnosed acute myeloid leukemia. Materials & methods: A network meta-analysis following a systematic literature review. RESULTS: In base-case analyses, GO + DA was associated with significantly greater overall survival and relapse-free survival versus most comparators, and similar rates of complete remission versus all evaluated comparators. Similar findings were seen in the subgroup analyses. Grade 3+ bleeding and hepatic events were higher with GO + DA versus some comparators, consistent with GO's profile. No differences were found for other evaluated outcomes. CONCLUSION: GO + DA provides significant overall survival and relapse-free survival benefit versus evaluated induction regimens for newly diagnosed acute myeloid leukemia.

Safety and effectiveness of classical and alternative sunitinib dosing schedules for metastatic renal cell carcinoma: a meta-analysis.

The optimal dosing schedule to maintain the effectiveness of sunitinib for metastatic renal cell carcinoma - while reducing toxicity - remains an important clinical question. A meta-analysis of randomized trials and observational studies assessed the relative treatment effects of 4/2, 2/1 and transitional-2/1 schedules on outcomes and adverse events using Bayesian network meta-analysis methods. Treatment with 2/1 reduced the risk of disease progression or death by 25% and had lower odds of hand-and-foot syndrome compared with the 4/2. A numerical but not 'statistical' benefit in progression-free survival was observed with the transitional-2/1 compared with 4/2. Alternative schedules with the 2/1 and transitional-2/1 may be more clinically beneficial in metastatic renal cell carcinoma than the 4/2 schedule.

Prolonged versus standard-duration venous thromboprophylaxis in major orthopedic surgery: a systematic review.

BACKGROUND: The optimal duration of thromboprophylaxis after major orthopedic surgery is unclear. PURPOSE: To compare the benefits and harms of prolonged versus standard-duration thromboprophylaxis after major orthopedic surgery in adults. DATA SOURCES: Cochrane Central Register of Controlled Trials and Scopus from 1980 to July 2011 and MEDLINE from 1980 through November 2011, without language restrictions. STUDY SELECTION: Randomized trials reporting thromboembolic or bleeding outcomes that compared prolonged (≥21 days) with standard-duration (7 to 10 days) thromboprophylaxis. DATA ABSTRACTION: Two independent reviewers abstracted data and rated study quality and strength of evidence. DATA SYNTHESIS: Eight randomized, controlled trials (3 good-quality and 5 fair-quality) met the inclusion criteria. High-strength evidence showed that compared with standard-duration therapy, prolonged prophylaxis resulted in fewer cases of pulmonary embolism (PE) (5 trials; odds ratio [OR], 0.14 [95% CI, 0.04 to 0.47]; absolute risk reduction [ARR], 0.8%), asymptomatic deep venous thrombosis (DVT) (4 trials; relative risk [RR], 0.48 [CI, 0.31 to 0.75]; ARR, 5.8%), symptomatic DVT (4 trials; OR, 0.36 [CI, 0.16 to 0.81]; ARR, 1.5%), and proximal DVT (6 trials; RR, 0.29 [CI, 0.16 to 0.52]; ARR, 7.1%). Moderate-strength evidence showed fewer symptomatic objectively confirmed episodes of venous thromboembolism (4 trials; RR, 0.38 [CI, 0.19 to 0.77]; ARR, 5.7%), nonfatal PE (4 trials; OR, 0.13 [CI, 0.03 to 0.54]; ARR, 0.7%), and DVT (7 trials; RR, 0.37 [CI, 0.21 to 0.64]; ARR, 12.1%) with prolonged prophylaxis. High-strength evidence showed more minor bleeding events with prolonged prophylaxis (OR, 2.44 [CI, 1.41 to 4.20]; absolute risk increase, 6.3%), and insufficient evidence from 1 trial on hip fracture surgery suggested more surgical-site bleeding events (OR, 7.55 [CI, 1.51 to 37.64]) with prolonged prophylaxis. LIMITATIONS: Data relevant to knee replacement or hip fracture surgery were scant and insufficient. Most trials had few events; the strength of evidence ratings that were used may not adequately capture uncertainty in such situations. CONCLUSION: Prolonged prophylaxis decreases the risk for venous thromboembolism, PE, and DVT while increasing the risk for minor bleeding in patients undergoing total hip replacement.

Systematic review: comparative effectiveness of adjunctive devices in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention of native vessels.

BACKGROUND: During percutaneous coronary intervention (PCI), dislodgement of atherothrombotic material from coronary lesions can result in distal embolization, and may lead to increased major adverse cardiovascular events (MACE) and mortality. We sought to systematically review the comparative effectiveness of adjunctive devices to remove thrombi or protect against distal embolization in patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI of native vessels. METHODS: We conducted a systematic literature search of Medline, the Cochrane Database, and Web of Science (January 1996-March 2011), http://www.clinicaltrials.gov, abstracts from major cardiology meetings, TCTMD, and CardioSource Plus. Two investigators independently screened citations and extracted data from randomized controlled trials (RCTs) that compared the use of adjunctive devices plus PCI to PCI alone, evaluated patients with STEMI, enrolled a population with 95% of target lesion(s) in native vessels, and reported data on at least one pre-specified outcome. Quality was graded as good, fair or poor and the strength of evidence was rated as high, moderate, low or insufficient. Disagreement was resolved through consensus. RESULTS: 37 trials met inclusion criteria. At the maximal duration of follow-up, catheter aspiration devices plus PCI significantly decreased the risk of MACE by 27% compared to PCI alone. Catheter aspiration devices also significantly increased the achievement of ST-segment resolution by 49%, myocardial blush grade of 3 (MBG-3) by 39%, and thrombolysis in myocardial infarction (TIMI) 3 flow by 8%, while reducing the risk of distal embolization by 44%, no reflow by 48% and coronary dissection by 70% versus standard PCI alone. In a majority of trials, the use of catheter aspiration devices increased procedural time upon qualitative assessment.Distal filter embolic protection devices significantly increased the risk of target revascularization by 39% although the use of mechanical thrombectomy or embolic protection devices did not significantly impact other final health outcomes. Distal balloon or any embolic protection device increased the achievement of MBG-3 by 61% and 20% and TIMI3 flow by 11% and 6% but did not significantly impact other intermediate outcomes versus control. Upon qualitative analysis, all device categories, with exception of catheter aspiration devices, appear to significantly prolong procedure time compared to PCI alone while none appear to significantly impact ejection fraction. Many of the final health outcome and adverse event evaluations were underpowered and the safety of devices overall is unclear due to insufficient amounts of data. CONCLUSIONS: In patients with STEMI, for most devices, few RCTs evaluated final health outcomes over a long period of follow-up. Due to insufficient data, the safety of these devices is unclear.

Efficacy and safety of front-line treatments for advanced Hodgkin lymphoma: a systematic literature review.

OBJECTIVE: To assess evidence on the safety and efficacy of ABVD (doxorubicin [Adriamycin®], bleomycin, vinblastine, and dacarbazine), BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and A+AVD (brentuximab vedotin, with doxorubicin, vinblastine, and dacarbazine) for advanced-stage Hodgkin lymphoma (HL). METHODS: A systematic literature review (SLR) was conducted on 29 July 2016 (updated 26 July 2018) to identify randomized controlled trials (RCTs) and non-RCTs assessing the treatment of newly-diagnosed advanced-stage HL with ABVD and BEACOPP (and their variants), and A+AVD. RESULTS: The SLR identified 62 RCTs and 42 non-RCTs. Five-year overall survival rates for ABVD and BEACOPP were 60-97% and 84-99%, and 5-year progression-free survival rates were 58-81% and 83-96%, respectively. Both regimens were associated with tolerability issues and side effects. Discontinuation or dose reduction of bleomycin resulted in fewer adverse events, without significantly affecting efficacy. A head-to-head trial demonstrated improved efficacy for A+AVD vs ABVD, with an acceptable tolerability profile. No data from head-to-head trials comparing A+AVD with BEACOPP were available, and an indirect treatment comparison was not feasible. CONCLUSION: New therapies, such as A+AVD, maintain the efficacy observed with current treatments, and may provide a more tolerable treatment option for patients with advanced-stage HL.

A Systematic Review of Network Meta-Analyses and Real-World Evidence Comparing Apixaban and Rivaroxaban in Nonvalvular Atrial Fibrillation.

There is no direct evidence comparing the 2 most commonly prescribed direct oral anticoagulants, apixaban and rivaroxaban, used for stroke prevention in nonvalvular atrial fibrillation (NVAF). A number of network meta-analyses (NMAs) of randomized control trials and real-world evidence (RWE) studies comparing the efficacy, effectiveness, and safety of apixaban and rivaroxaban have been published; however, a comprehensive evidence review across the available body of evidence is lacking. In this study, we aimed to systematically review and evaluate the clinical outcomes of apixaban and rivaroxaban using a combination of data gleaned from both NMAs and RWE studies. The review identified 21 NMAs and 5 RWE studies. The data demonstrated that apixaban was associated with fewer major bleeding events compared to rivaroxaban. There was no difference in the efficacy/effectiveness profiles between these treatments. Bleeding is a serious complication of anticoagulation therapy for the management of NVAF, and is associated with increased rates of hospitalization, morbidity, mortality, and health-care expenditure. The majority of studies in this comprehensive evidence review suggests that apixaban has a lower risk of major bleeding events compared to rivaroxaban in patients with NVAF.

Comparative effectiveness of combined pharmacologic and mechanical thromboprophylaxis versus either method alone in major orthopedic surgery: a systematic review and meta-analysis.

STUDY OBJECTIVE: To evaluate the comparative efficacy and safety of combination pharmacologic and mechanical venous thromboembolism (VTE) prophylaxis versus either method alone in major orthopedic surgery. DESIGN: Systematic review with meta-analysis of six randomized controlled trials. PATIENTS: Patients undergoing total hip replacement, total knee replacement, or hip fracture surgery who received VTE prophylaxis. MEASUREMENTS AND MAIN RESULTS: We conducted a systematic literature search of the MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus databases (January 1980-July 2011) to identify trials that directly compared pharmacologic plus mechanical VTE prophylaxis to either strategy alone, evaluated United States Food and Drug Administration-approved agents, and reported rates of mortality, VTE, bleeding, and other adverse effects. Six trials were included, none of which were conducted in patients who had hip fracture surgery. The quality of each trial was evaluated, and the strength of evidence for each outcome was rated. No significant difference was found in the rate of pulmonary embolism or nonfatal pulmonary embolism when the combination of pharmacologic and mechanical prophylaxis was compared to pharmacologic prophylaxis alone, with low strength of evidence. The risk of deep vein thrombosis (DVT) was significantly decreased in the combination group (relative risk [RR] 0.48 [95% confidence interval (CI) 0.32-0.72]), with moderate strength of evidence, with benefits of combination therapy persisting in the total knee replacement subgroup (RR 0.41 [95% CI 0.25-0.68]). There was insufficient evidence to evaluate other final or intermediate outcomes or harms. In the comparison of combined pharmacologic and mechanical prophylaxis to mechanical prophylaxis alone, there was insufficient evidence to evaluate any final health outcomes or harms. There was no significant difference in the risk of proximal DVT when comparing combination prophylaxis to mechanical prophylaxis alone (RR 0.78 [95% CI 0.35-1.74]) based on low strength of evidence. CONCLUSIONS: The risk of DVT was decreased with the use of combination prophylaxis versus pharmacologic prophylaxis alone in patients undergoing total hip replacement or total knee replacement. However, due to primarily insufficient evidence for most outcomes evaluated, the balance of benefits to harms of combined pharmacologic and mechanical prophylaxis versus either strategy alone cannot be determined in patients undergoing major orthopedic surgery.

Height and risk of heart failure in the Physicians' Health Study.

Although previous studies have reported an association between height and cardiovascular disease, it is unclear whether height is associated with the risk of heart failure (HF). We hypothesized that height would be inversely associated with HF risk. We used prospective data from 22,042 male physicians (mean age 53.8 years) from the Physicians' Health Study. Height was self-reported at baseline. Incident HF was ascertained using follow-up questionnaires and validated through review of the medical records in a subsample. The Cox proportional hazard model was used to compute the hazard ratio (HR) and corresponding 95% confidence interval (CI). The mean height ± SD was 1.78 ± 0.07 m. A total of 1,444 HF cases occurred during a mean follow-up of 22.3 years. Compared to subjects in the lowest height category (1.40 to 1.73 m), the HR for HF was 0.86 (95% CI 0.74 to 0.99), 0.82 (95% CI 0.70 to 0.95), and 0.76 (95% CI 0.63 to 0.91) for the height categories of 1.74 to 1.78 m, 1.79 to 1.83 m, and 1.84 to 2.08 m, respectively, after adjustment for age, weight, hypertension, and diabetes mellitus (p for trend = 0.0023). The HR per SD increment in height was 0.92 (95% CI 0.86 to 0.98) in a fully adjusted model. The exclusion of those with prevalent atrial fibrillation, left ventricular hypertrophy, valvular heart disease, and a history of coronary artery bypass grafting yielded similar results (HR per SD 0.88, 95% CI 0.83 to 0.94). In conclusion, our data demonstrated an inverse association between height and incident HF in United States male physicians. Additional studies to elucidate the underlying biologic mechanisms are warranted.

Efficacy and safety of innovator versus generic drugs in patients with epilepsy: a systematic review.

Generic antiepileptic drugs achieve blood concentrations similar to those of innovator drugs in healthy volunteers, but their comparative effectiveness has not been well evaluated. Thus, we assessed the efficacy, tolerability, and safety of innovator versus generic antiepileptic drugs. We searched the MEDLINE database, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science for studies that evaluated innovator and generic antiepileptic drugs in patients with epilepsy and reported data on prespecified outcomes. We extracted data on study design, interventions, quality criteria, study population, baseline characteristics, and outcomes. Compared with initiation of innovator antiepileptic drugs, initiation of generic antiepileptic drugs did not significantly alter seizure occurrence (relative risk [RR] 0.87, 95% confidence interval [CI] 0.64-1.18; strength of evidence: low) or frequency (standardized mean difference 0.03, 95% CI -0.08-0.14; strength of evidence: low), withdrawals due to lack of efficacy (RR 1.02, 95% CI 0.41-2.54; strength of evidence: low) or adverse events (RR 0.79, 95% CI 0.28-2.20; strength of evidence: low), pharmacokinetic concentrations (maximum, minimum, or area under the curve [strength of evidence: low]), or a myriad of adverse events (strength of evidence: low or insufficient) in clinical trials. In qualitatively evaluated observational studies, switching between forms of antiepileptic drug (innovator to generic, generic to generic) may increase the risk of hospitalization (strength of evidence: low), hospital stay duration (strength of evidence: low), and a composite end point of medical service utilization (strength of evidence: insufficient) but may not increase outpatient service utilization (strength of evidence: low). Data are limited predominantly to carbamazepine, phenytoin, and valproic acid. Clinical trials are limited by small sample size, short-term nature, and lack of specification of A-rated generic products (generics that the United States Food and Drug Administration has deemed bioequivalent to the innovator drug). Observational trials lack full accounting for confounders and have inherent limitations. With a low strength of evidence, it appears that initiating an innovator or generic antiepileptic drug will provide similar efficacy, tolerability, and safety but that switching from one form to the other may be associated with more hospitalizations and longer hospital stays.

Comparative effectiveness of low-molecular-weight heparins versus other anticoagulants in major orthopedic surgery: a systematic review and meta-analysis.

STUDY OBJECTIVE: To evaluate the comparative efficacy and safety of low-molecular-weight heparins (LMWHs) versus other anticoagulants as venous thromboembolism prophylaxis in major orthopedic surgery. DESIGN: Systematic review with meta-analysis of 37 randomized controlled trials. PATIENTS: Patients undergoing total hip replacement, total knee replacement, or hip fracture surgery who received prophylaxis with a LMWH or another anticoagulant. MEASUREMENTS AND MAIN RESULTS: We conducted a systematic literature search of the MEDLINE, Cochrane Central Register of Controlled Trials, and Scopus databases (1980-July 2011) to identify randomized controlled trials. Trials were included if they directly compared LMWH prophylaxis with another anticoagulant class and reported outcomes of interest. Compared with patients who received unfractionated heparin (UFH), patients who received LMWHs had fewer pulmonary embolism, total deep vein thrombosis (DVT), major bleeding, and heparin-induced thrombocytopenia events. Compared with patients who received vitamin K antagonists (VKAs), patients who received LMWHs had fewer total DVT and distal DVT events but reported increased major bleeding, minor bleeding, and surgical site bleeding events. Major efficacy end points such as symptomatic venous thromboembolism, pulmonary embolism, and nonfatal pulmonary embolism showed similar benefits of therapy with LMWHs and VKAs. Compared with patients receiving factor Xa inhibitors, patients who received LMWHs had more major venous thromboembolism, pulmonary embolism, total DVT, asymptomatic DVT, proximal DVT, and distal DVT events but fewer major bleeding events. Compared with patients receiving direct thrombin inhibitors (DTIs), patients who received LMWHs had more major venous thromboembolism, total DVT, and proximal DVT events without significantly negatively affecting bleeding. However, patients who received LMWHs had fewer distal DVT events versus those who received DTIs. Subgroup analyses indicated differences based on the surgical procedure and individual drug within certain pharmacologic classes. CONCLUSION: According to moderate-to-high strength of evidence, LMWH prophylaxis provides additional benefits with less harm compared with UFH. With predominantly moderate strength of evidence, the balance of benefits to harms for factor Xa inhibitors or DTIs compared with LMWHs seems favorable. With predominantly low-to-moderate strength of evidence, the known benefits in total DVT and distal DVT with LMWHs versus VKAs may not be sufficient to counteract the increased risk of bleeding.

Association between CHADS2risk factors and anticoagulation-related bleeding: a systematic literature review.

OBJECTIVE: To determine the strength of evidence supporting an accentuated bleeding risk when patients with CHADS(2) risk factors (chronic heart failure, hypertension, advanced age, diabetes, and prior stroke/transient ischemic attack) receive warfarin. METHODS: A systematic literature search of MEDLINE (January 1, 1950, through December 22, 2009) and Cochrane CENTRAL (through December 22, 2009) was conducted to identify studies that reported multivariate results on the association between CHADS(2) covariates and risk of bleeding in patients receiving warfarin. Each covariate was evaluated for its association with a specific type of bleeding. Individual evaluations were rated as good, fair, or poor using methods consistent with those recommended by the Agency for Healthcare Research and Quality. The strength of the associations between each CHADS(2) covariate and a specific type of bleeding was determined using Grading of Recommendations Assessment, Development and Evaluation criteria as insufficient, very low, low, moderate, or high for the entire body of evidence. RESULTS: Forty-one studies were identified, reporting 127 multivariate evaluations of the association between a CHADS(2) covariate and bleeding risk. No CHADS(2) covariate had a high strength of evidence for association with any bleeding type. For the vast majority of evaluations, the strength of evidence between covariates and bleeding was low. Advanced age was the only covariate that had a moderate strength of evidence for association; this was the strongest independent positive predictor for major bleeding. Similar findings were observed regardless of whether all included studies, or only those evaluating patients with atrial fibrillation, were assessed. CONCLUSION: The associations between CHADS(2) covariates and increased bleeding risk were weak, with the exception of age. Given the known association of the CHADS(2) score and stroke risk, the decision to prescribe warfarin should be driven more by patients' risk of stroke than by the risk of bleeding.