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1.  Trade-offs in quality of life and survival with chemotherapy for advanced breast cancer: mature results of a randomized trial comparing single-agent mitoxantrone with combination cyclophosphamide, methotrexate, 5-fluorouracil and prednisone 
SpringerPlus  2013;2:391.
We evaluate trade-offs between quality of life (QoL) and survival improvement for two chemotherapy regimens in advanced breast cancer. We also report on the long-term survival of patients in the ANZ 8614 clinical trial.
A total of 391 patients were randomized to mitoxantrone (14 mg/m2 intravenously every 21 days) or a combination of cyclophosphamide 100 mg/m2 and prednisone 40 mg/m2 orally days 1 to 14 plus methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously days 1 and 8 every 28 days (CMFP). QoL was self-assessed on 14 linear analog scales. We computed the mean differences between the two treatments as products of the mean differences in global QoL, progression-free survival and overall survival.
CMFP led to a higher overall tumor response (39% vs. 25%, P=0.004) and longer progression-free survival (PFS) (median 5.6 vs 3.9 months, P=0.02) but with significantly more toxicity from alopecia, mucositis, diarrhea, anemia and lethargy. Overall survival (OS) was similar in the two groups (median 10.1 vs 11.6 months, P=0.81). QoL over the first 12 weeks was rated better by patients on CMFP for mood (P=0.04), nausea and vomiting (P=0.01), and feeling sick (P=0.02) but worse for hair loss (P<0.0001). A weighted combination of individual QoL items favoured CMFP (subset score mean difference 2.4, P=0.03). A global QoL score tended to favour CMFP (global score mean difference 1.7, P=0.18). Quality-adjusted PFS was significantly longer with CMFP (mean 7.208 vs 5.965 months, P=0.04), but quality-adjusted OS was not significantly different (mean 11.832 vs 11.315 months, P=0.57).
Despite the greater toxicity, the superior antitumor activity of CMFP led to an overall improvement in quality-adjusted PFS. In advanced breast cancer, in clinical decision making about treatment for palliative intent, the principle used to assess trade-offs between antitumor efficacy and toxicity remains relevant and applicable to all modern therapeutic agents.
PMCID: PMC3765591  PMID: 24024086
Breast cancer; Chemotherapy; Quality of life; Toxicity; Survival; Randomized trial
2.  Which lipid measurement should we monitor? An analysis of the LIPID study 
BMJ Open  2014;4(2):e003512.
To evaluate the optimal lipid to measure in monitoring patients, we assessed three factors that influence the choice of monitoring tests: (1) clinical validity; (2) responsiveness to therapy changes and (3) the size of the long-term ‘signal-to-noise’ ratio.
Longitudinal analyses of repeated lipid measurement over 5 years.
Subsidiary analysis of a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study—a clinical trial in Australia, New Zealand and Finland.
9014 patients aged 31–75 years with previous acute coronary syndromes.
Patients were randomly assigned to 40 mg daily pravastatin or placebo.
Primary and secondary outcome measures
We used data on serial lipid measurements—at randomisation, 6 months and 12 months, and then annually to 5 years—of total cholesterol; low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and their ratios; triglycerides; and apolipoproteins A and B and their ratio and their ability to predict coronary events.
All the lipid measures were statistically significantly associated with future coronary events, but the associations between each of the three ratio measures (total or LDL cholesterol to HDL cholesterol, and apolipoprotein B to apolipoprotein A1) and the time to a coronary event were better than those for any of the single lipid measures. The two cholesterol ratios also ranked highly for the long-term signal-to-noise ratios. However, LDL cholesterol and non-HDL cholesterol showed the most responsiveness to treatment change.
Lipid monitoring is increasingly common, but current guidelines vary. No single measure was best on all three criteria. Total cholesterol did not rank highly on any single criterion. However, measurements based on cholesterol subfractions—non-HDL cholesterol (total cholesterol minus HDL cholesterol) and the two ratios—appeared superior to total cholesterol or any of the apolipoprotein options. Guidelines should consider using non-HDL cholesterol or a ratio measure for initial treatment decisions and subsequent monitoring.
PMCID: PMC3931993  PMID: 24561494
Public Health; Epidemiology; Vascular Medicine
3.  Benefits and Safety of Long-Term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment 
Diabetes Care  2012;35(2):218-225.
Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m2) are at particular cardiovascular risk. Fenofibrate’s safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate’s effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study.
Type 2 diabetic patients (aged 50–75 years) with eGFR ≥30 mL/min/1.73 m2 were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30–59, 60–89, and ≥90 mL/min/1.73 m2). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 μmol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat.
Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment.
Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.
PMCID: PMC3263870  PMID: 22210576
4.  Using patient management as a surrogate for patient health outcomes in diagnostic test evaluation 
Before a new test is introduced in clinical practice, evidence is needed to demonstrate that its use will lead to improvements in patient health outcomes. Studies reporting test accuracy may not be sufficient, and clinical trials of tests that measure patient health outcomes are rarely feasible. Therefore, the consequences of testing on patient management are often investigated as an intermediate step in the pathway. There is a lack of guidance on the interpretation of this evidence, and patient management studies often neglect a discussion of the limitations of measuring patient management as a surrogate for health outcomes.
We discuss the rationale for measuring patient management, describe the common study designs and provide guidance about how this evidence should be reported.
Interpretation of patient management studies relies on the condition that patient management is a valid surrogate for downstream patient benefits. This condition presupposes two critical assumptions: the test improves diagnostic accuracy; and the measured changes in patient management improve patient health outcomes. The validity of this evidence depends on the certainty around these critical assumptions and the ability of the study design to minimise bias. Three common designs are test RCTs that measure patient management as a primary endpoint, diagnostic before-after studies that compare planned patient management before and after testing, and accuracy studies that are extended to report on the actual treatment or further tests received following a positive and negative test result.
Patient management can be measured as a surrogate outcome for test evaluation if its limitations are recognised. The potential consequences of a positive and negative test result on patient management should be pre-specified and the potential patient benefits of these management changes clearly stated. Randomised comparisons will provide higher quality evidence about differences in patient management using the new test than observational studies. Regardless of the study design used, the critical assumption that patient management is a valid surrogate for downstream patient benefits or harms must be discussed in these studies.
PMCID: PMC3313870  PMID: 22333319
5.  Sex Differences in Mortality Following Acute Coronary Syndromes 
There is conflicting information about whether sex-differences modulate short-term mortality following acute coronary syndromes (ACS).
To investigate the relationship between sex and 30-day mortality in ACS, and determine whether this relationship is modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.
Design Setting and Participants
Data from 11 ACS trials from 1993 to 2006 were pooled. Of 136,247 patients, 38,048 (28%) were women; 102,004 (26% women) STEMI, 14,466 (29% women) NSTEMI and 19,777 (40% women) unstable angina (UA).
Main Outcome Measure
Thirty-day mortality following ACS.
Mortality at 30 days was 9.6% in women and 5.3% in men (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.83–2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR 1.06, 95% CI 0.99–1.15). Importantly, a significant sex by type of ACS interaction was demonstrated (P<0.001). In STEMI, 30-day mortality was higher among women (adjusted OR 1.15, 95% CI 1.06–1.24), whereas NSTEMI (adjusted OR 0.77, 95% CI 0.63–0.95), and UA mortality was lower among women (adjusted OR 0.55, 95% CI 0.43–0.70). In a cohort of 35,128 patients with angiographic data, women more often had non-obstructive (15% vs. 8%,) and less often had 2-vessel (25% vs. 28%) and 3-vessel (23% vs. 26%) coronary disease regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (p-value for interaction =0.70),
Sex-based differences exist in 30-day mortality among ACS patients and vary depending on clinical presentation. However, these differences are markedly attenuated following adjustment for clinical differences and angiographic data.
PMCID: PMC2778841  PMID: 19706861

Results 1-5 (5)