Robert G. Metcalf

Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use

Background The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a ‘treat-to-target’ protocol of combination disease-modifying anti-rheumatic drugs (DMARDs). Methods Patients with RA <12 months’ duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4 g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy. Results In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti–cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events. Conclusions FO was associated with benefits additional to those achieved by combination ‘treat-to-target’ DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.

Effect of Dietary n-3 Polyunsaturated Fatty Acids on the Inducibility of Ventricular Tachycardia in Patients With Ischemic Cardiomyopathy

Increased consumption of fish and/or fish oil was associated with decreased risk of sudden cardiac death (SCD). The study aim was to evaluate the antiarrhythmic effect of dietary fish oil on the inducibility of ventricular tachycardia (VT) at high risk of SCD. Patients with coronary artery disease undergoing defibrillator implantation were recruited if sustained monomorphic VT could be induced by programmed extra stimuli at 2 cycle lengths. After the initial study, 12 patients consumed 3 g/d of encapsulated fish oil for approximately 6 weeks before a repeated electrophysiologic study. To control for fluctuations in the inducibility of VT, an additional 14 patients with no dietary manipulation were also studied. Aggressiveness of stimulation required to induce VT was ranked from least aggressive to most aggressive based on cycle length and number of extra stimuli, with noninducibility ranked highest. At the repeated electrophysiologic study, in the fish-oil group, 42% had no inducible VT, 42% required more aggressive stimulation to induce VT, 8% required identical stimulation, and 8% required less stimulation compared with 7%, 36%, 36%, and 21% in the control group, respectively. Overall, there was a change to noninducible or less inducible VT in the fish-oil group, but no change in the control group (p = 0.003 and p = 0.65, respectively; Wilcoxons sign-rank test). In conclusion, dietary n-3 fatty acid supplementation decreased the inducibility of VT in patients at risk of SCD. These findings suggest that dietary fish oil can have an antiarrhythmic effect.

Effect of Dietary Fish Oil on Atrial Fibrillation After Cardiac Surgery

An open-label study reported that ingestion of a fish oil concentrate decreased the incidence of atrial fibrillation (AF) after coronary artery bypass grafting (CABG) surgery. However, a general cardiac surgery population involves valve and CABG surgeries. We undertook a double-blinded randomized controlled trial to examine the effectiveness of fish oil supplementation on the incidence of postsurgical AF after CABG and valve procedures. The primary end point was incidence of AF in the first 6 days after surgery. Two hundred patients were randomized to receive fish oil (providing 4.6 g/day of long-chain ω-3 fatty acids) or a control oil starting 3 weeks before surgery; 194 subjects completed the study, with 47 of 97 subjects in the control group and 36 of 97 subjects in the fish oil group developing AF (odds ratio 0.63, 95% confidence interval [CI] 0.35 to 1.11). There was a nonstatistically significant delay in time to onset of AF in the fish oil group (hazard ratio 0.66, 95% CI 0.43 to 1.01). There was a significant decrease in mean length of stay in the intensive care unit in the fish oil group (ratio of means 0.71, 95% CI 0.56 to 0.90). In conclusion, in a mixed cardiac surgery population, supplementation with dietary fish oil did not result in a significant decrease in the incidence of postsurgical AF. However, there was a significant decrease in time spent in the intensive care unit.

Relation between blood and atrial fatty acids in patients undergoing cardiac bypass surgery

BACKGROUND Studies relating cardiovascular outcomes to dietary or blood measures of various fatty acids rely on the implicit assumptions that dietary change results in changes in blood fatty acids that, in turn, alter cardiac fatty acids. Although dietary intakes of n-3 (omega-3), n-6 (omega-6), and trans fatty acids are reflected in their concentrations in blood, there are few human data on the relation between blood and cardiac concentrations of fatty acids. OBJECTIVE The objective was to explore relations between blood and myocardial n-3, n-6, trans, monosaturated, and saturated fatty acids over a range of community intakes to evaluate whether blood fatty acids are useful surrogate markers of their cardiac counterparts. DESIGN Patients undergoing on-pump coronary bypass surgery were recruited. Right atrial appendages and blood were collected at surgery for fatty acid analysis. RESULTS Atrial appendages and matching blood samples were collected from 61 patients. Highly significant correlations were identified between atrial and erythrocyte or plasma n-3 [eg, eicosapentaenoic acid (erythrocytes: r = 0.93, P < 0.0001; plasma: r = 0.87, P < 0.0001)], some n-6 [eg, arachidonic acid (erythrocytes: r = 0.45, P = 0.0003; plasma: r = 0.39, P = 0.002)], trans [eg, total trans 18:1 (erythrocytes: r = 0.89, P < 0.0001; plasma: r = 0.74, P < 0.0001)], and monounsaturated [eg, oleic acid (erythrocytes: r = 0.37, P = 0.003)] fatty acids. There were no statistical associations between blood and cardiac saturated fatty acids. CONCLUSION Erythrocyte- and plasma phospholipid-derived fatty acids can be used to estimate cardiac fatty acid status in humans.

Pitfalls in the use of randomised controlled trials for fish oil studies with cardiac patients

Randomised controlled trials (RCT) examining the effects of fish oil supplementation on cardiac outcomes have yielded varying results over time. Although RCT are placed at the top of the evidence hierarchy, this methodology arose in the framework of pharmaceutical development. RCT with pharmaceuticals differ in important ways from RCT involving fish oil interventions. In particular, in pharmaceutical RCT, the test agent is present only in the intervention group and not in the control group, whereas in fish oil RCT, n-3 fats are present in the diet and in the tissues of both groups. Also, early phase studies with pharmaceuticals determine pharmacokinetics and pharmacodynamics to design the dose of the RCT intervention so that it is in a predicted linear dose-response range. None of this happens in fish oil RCT, and there is evidence that both baseline n-3 intake and tissue levels may be sufficiently high in the dose-response range that it is not possible to demonstrate a clinical effect with a RCT. When these issues are considered, it is possible that the changing pattern of fish consumption and fish oil use over time, especially in cardiac patients, can explain the disparity where benefit was observed in the early fish oil trials but not in the more recent trials.

Atrial protective effects of n-3 polyunsaturated fatty acids: A long-term study in ovine chronic heart failure

BACKGROUND It has been suggested that omega-3 polyunsaturated fatty acids (n-3 PUFAs) may prevent the development of atrial fibrillation (AF). OBJECTIVE The purpose of this study was to evaluate the impact of these agents on development of the AF substrate in heart failure (HF). METHODS In this study, HF was induced by intracoronary doxorubicin infusions. Twenty-one sheep [7 with n-3 PUFAs treated HF (HF-PUFA), 7 with olive oil-treated HF controls (HF-CTL), 7 controls (CTL)] were studied. Open chest electrophysiologic study was performed with assessment of biatrial effective refractory period (ERP) and conduction. Cardiac function was monitored by magnetic resonance imaging. Atrial n-3 PUFAs levels were quantified using chromatography. Structural analysis was also performed. RESULTS Atrial n-3 PUFAs levels were twofold to threefold higher in the HF-PUFA group. n-3 PUFAs prevented the development of HF-related left atrial enlargement (P = .001) but not left ventricular/atrial dysfunction. Atrial ERP was significantly lower in the HF-PUFA group (P <.001), but ERP heterogeneity was unchanged. In addition, n-3 PUFAs suppressed atrial conduction abnormalities seen in HF of prolonged P-wave duration (P = .01) and slowed (P <.001) and heterogeneous (P <.05) conduction. The duration of induced AF episodes in HF-PUFA was shorter (P = .02), although AF inducibility was unaltered (P = NS). A 20% reduction of atrial interstitial fibrosis was seen in the HF-PUFA group (P <.05). CONCLUSION In this ovine HF study, chronic n-3 PUFAs use protected against adverse atrial remodeling by preventing atrial enlargement, fibrosis, and conduction abnormalities leading to shorter AF episodes despite lower ERP.

Characterising deviation from treat-to-target strategies for early rheumatoid arthritis: the first three years

IntroductionTreat-to-target (T2T) strategies using a protocol of pre-defined adjustments of disease-modifying anti-rheumatic drugs (DMARDs) according to disease activity improve outcomes for patients with rheumatoid arthritis (RA). However, successful implementation may be limited by deviations from the protocol. The aim of this study was to determine the prevalence of protocol deviation, explore the reasons and identify subsets of patients in whom treatment protocols are more difficult to follow.MethodsIn this retrospective cohort study, treatment-naïve patients with RA of less than one year’s duration, attending a dedicated early arthritis clinic between 2001 and 2013, were followed for three years from initiation of combination therapy with conventional DMARDs which was subsequently modified according to a T2T protocol. At each clinic visit, whether deviation from the protocol occurred, the type of deviation and the reasons for deviation were assessed. The relationship between protocol deviations and baseline variables was determined using linear regression analysis.ResultsIn total, 198 patients contributed 3,654 clinic visits. The prevalence of protocol deviations was 24.5% and deviation in at least at one clinic visit was experienced by 90.4% of patients. The median time to first deviation was 30 weeks. Continuing existing treatment rather than intensifying therapy was the most common type of deviation (59.9%). Patient and physician related factors were the most common reasons for deviation, each accounting for 24.7% of deviations, followed by toxicities (23.3%) and comorbidities (20.0%). The prevalence of protocol deviations was lower among patients who achieved remission after three years (13.1%; 162 deviations out of 1,228 visits) compared with those who were not in remission (30.9%; 523/1692) (P <0.0001). On multivariate analysis, only body mass index (P = 0.003) and helplessness score (P = 0.04) were independent predictors of protocol deviations although the predictive power of the model was not strong (R2 = 0.17).ConclusionsDeviation from a T2T protocol occurred in one quarter of visits, indicating that applying the T2T approach is feasible in clinical practice. Failure to escalate dose when indicated was commonly encountered, and just under half of the observed deviations were related to either toxicities or comorbidities and were therefore justifiable on clinical grounds.

U-shaped relationship between tissue docosahexaenoic acid and atrial fibrillation following cardiac surgery.

Background/objectives:Randomised controlled trials (RCTs) evaluating the effect of fish oil supplementation on postoperative atrial fibrillation (POAF) following cardiac surgery have produced mixed results. In this study, we examined relationships between levels of red blood cell (RBC) n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) and the incidence of POAF.Subjects/methods:We used combined data (n=355) from RCTs conducted in Australia and Iceland. The primary end point was defined as POAF lasting >10 min in the first 6 days following surgery. The odds ratios (ORs) for POAF were compared between quintiles of preoperative RBC n-3 LC-PUFA levels by multivariable logistic regression.Results:Subjects with RBC docosahexaenoic acid (DHA) in the fourth quintile, comprising a RBC DHA range of 7.0–7.9%, had the lowest incidence of POAF. Subjects in the lowest and highest quintiles had significantly higher risk of developing POAF compared with those in the fourth quintile (OR=2.36: 95% CI; 1.07–5.24 and OR=2.45: 95% CI; 1.16–5.17, respectively). There was no association between RBC eicosapentaenoic acid levels and POAF incidence.Conclusions:The results suggest a ‘U-shaped’ relationship between RBC DHA levels and POAF incidence. The possibility of increased risk of POAF at high levels of DHA suggests an upper limit for n-3 LC-PUFAs in certain conditions.

Determining the acceptable level of physician compliance with a treat‐to‐target strategy in early rheumatoid arthritis

To determine the minimum cut‐points for rate of physician compliance with a treat‐to‐target (T2T) strategy needed to achieve optimal rates of remission or low disease activity (LDA).

Effect of Adherence to Protocolized Targeted Intensifications of Disease-modifying Antirheumatic Drugs on Treatment Outcomes in Rheumatoid Arthritis: Results from an Australian Early Arthritis Cohort

Objective. To investigate the association between adherence to treat-to-target (T2T) protocol and disease activity, functional outcomes, and radiographic outcomes in early rheumatoid arthritis (RA). Methods. Data from a longitudinal cohort of patients with early RA were used. Adherence was determined at each followup visit over 3 years according to predefined criteria. The primary endpoint was remission according to Disease Activity Score in 28 joints (DAS28) and Simplified Disease Activity Index (SDAI) criteria. Functional and radiographic outcomes measured by modified Health Assessment Questionnaire and modified total Sharp score, respectively, were secondary endpoints. Results. A total of 198 patients with 3078 clinic visits over 3 years were included in this analysis. After adjusting for relevant variables, although there was no significant association between adherence to T2T and remission rate after 1 year, the associations reached significance after 3 years for both DAS28 (OR 1.71, 95% CI 1.16–2.50; p = 0.006) and SDAI criteria (OR 1.94, 95% CI 1.06–3.56; p = 0.033). After 3 years, adherence was also associated with improvement in physical function (β=0.12, 95% CI 0.06–0.18; p < 0.0001). None of the radiographic outcomes were associated with adherence after either 1 or 3 years, although there was a trend for higher adherence to be associated with less radiographic progression at the end of the study (p = 0.061). Conclusion. Increased adherence to T2T was associated with better longterm disease activity and functional outcomes, which suggests that the benefit of a T2T protocol may be enhanced by ensuring adequate adherence.