Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not ...been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe-and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials.
The Fontan Fitness Intervention Trial (F-FIT)-a phase III clinical trial-aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (<16 years) will be randomized to either a physical activity and exercise program of moderate-to-vigorous intensity or usual care in a two-arm trial with a 1:1 allocation. The primary outcome is a change in aerobic exercise capacity (peak oxygen uptake) at 4-months. Secondary outcomes include safety, and changes in cardiopulmonary exercise testing measures, peripheral venous pressure, respiratory muscle and lung function, body composition, liver stiffness, neuropsychological and neurocognitive function, physical activity levels, dietary and nutritional status, vascular function, neurohormonal activation, metabolites, cardiac function, quality of life, musculoskeletal fitness, and health care utilization. Outcome measures will be assessed at baseline, 4-months, and 12-months. This manuscript will describe the pathophysiology of exercise intolerance in the Fontan circulation and the rationale and protocol for the F-FIT.
Subgroup analysis in clinical trials Cook, David I; Gebski, Val J; Keech, Anthony C
Medical journal of Australia,
03/2004, Letnik:
180, Številka:
6
Journal Article
Randomisation in clinical trials Beller, Elaine M; Gebski, Val; Keech, Anthony C
Medical journal of Australia,
11/2002, Letnik:
177, Številka:
10
Journal Article
Data on PCSK9 inhibition in chronic kidney disease (CKD) is limited.
The purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function.
The FOURIER (Further ...Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or non-high-density lipoprotein cholesterol ≥100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate.
There were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with ≥stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio HR: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage ≥3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); p
= 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (p
= 0.75)-preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage ≥3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were -2.5% (95% CI: -0.4% to -4.7%) for stage ≥3 CKD compared with -1.7% (95% CI: 0.5% to -2.8%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage.
LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk FOURIER; NCT01764633).
The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular ...Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events.
FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia.
Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio HR 0.79; 95% confidence interval CI, 0.66-0.94;
=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93;
=0.0003;
=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91;
=0.0040) for those with PAD and 0.81 (0.73-0.90;
<0.0001) for those without PAD (
=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88;
=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (
=0.026 for the beta coefficient) that extended down to <10 mg/dL.
Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.
Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We ...undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages.
In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.
14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence.
Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials.
Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation.
The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) ...inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk.
We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab.
In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50-1.00;
=0.05), with no effect in the 1st year (HR, 0.96 95% CI, 0.57-1.62) but a 46% reduction (HR, 0.54 95% CI, 0.33-0.88;
=0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 95% CI, 0.53-0.90;
=0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lpa) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 95% CI, 0.30-0.89;
=0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk (
0.087 for HR;
0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (
=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (
=0.04) and absolute VTE reduction (
=0.009) in comparison with those without high genetic risk.
PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.
ABSTRACT
Objective: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim ...of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting.
Methods: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista† (CORE) trial. MORE was an international, 4‐year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4‐year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test.
†Evista is a registered trade name of Eli Lilly and Company, Indianapolis, USA
Results: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups ( p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively ( p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93–3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups ( p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo ( p = 0.028, p < 0.001, and p = 0.008, respectively).
Conclusion: These 8‐year data support the known clinical safety profile of raloxifene, established in the MORE trial.
Oestrogen replacement therapy is associated with a marked reduction in coronary event rates in post-menopausal women. As older age is associated with progressive arterial endothelial damage, a key ...event in atherosclerosis, we assessed whether hormone replacement therapy (HRT) with oestrogen alone, or oestrogen and progesterone combined, is associated with improved endothelial function in healthy women after the menopause.
Using high resolution external vascular ultrasound, brachial artery diameter was measured at rest and in response to reactive hyperaemia, with increased flow causing endothelium-dependent dilatation (flow-mediated dilatation).
We investigated 135 healthy women; 40 were pre-menopausal (mean +/- SD age/26 +/- 6 years, group 1), 40 were post-menopausal and had never taken HRT (aged 58 +/- 3 years; group 2) and 55 were age-matched post-menopausal women who had taken HRT for > or = 2 years, from within 2 years of the menopause (aged 57 +/- 4 years; group 3). In group 3, 40 women were on combined oestrogen and progesterone and 15 on oestrogen-only HRT.
In group 2, flow-mediated dilatation was significantly reduced compared with group 1 (4.4 +/- 3.4 vs 9.6 +/- 3.6%, P < 0.001), consistent with a decline in arterial endothelial function after the menopause. In group 3, however, flow-mediated dilatation was significantly better than group 2 (6.2 +/- 3.3 vs 4.4 +/- 3.4%, P = 0.01), suggesting a protective effect of HRT. Flow-mediated dilatation was similar in women taking oestrogen alone and in those on combined HRT (5.5 +/- 2.8 vs 6.5 +/- 3.4%, P = 0.40).
Long-term HRT is associated with improved arterial endothelial function in healthy post-menopausal women. This benefit was observed in both the combined hormone replacement and unopposed oestrogen therapy groups. This may explain some of the apparent cardioprotective effect of HRT after the menopause.
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