Jens Refsgaard

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Background— Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results— We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74–0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52–0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro–B-type natriuretic peptide and troponin) versus enalapril. Conclusions— Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

Aims Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. Methods and results We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality. Conclusion These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.

Carvedilol does not alter the insulin sensitivity in patients with congestive heart failure

Congestive heart failure (CHF) has previously been shown to be associated with insulin resistance and hyperinsulinemia. A beneficial effect of the non‐selective β‐blocker carvedilol has been demonstrated in patients with CHF. However, whether the drug affects the insulin sensitivity (Si) is unknown.

Ambulatory blood pressure monitoring after 1 year on valsartan or amlodipine-based treatment: a VALUE substudy.

Objective The ambulatory blood pressure (ABP) monitoring substudy of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was carried out in a subset of patients from USA, Italy and Denmark. ABP was measured after 1 year in the trial, with the aim of evaluating comparability of ABP levels on valsartan (VAL) and amlodipine (AML)-based regimens. Methods ABP was measured every 20 min during a 25-h period after morning administration of medicine; 659 patients were available for intention-to-treat analysis. Results Office blood pressure (BP) differences were smaller than in the main study and mean ABP levels also showed only minor differences between the two regimens (VAL, 132.5/74.8 mmHg; AML, 131.5/75.2 mmHg). However, during the first 7 h after dosing, ABP was lower on VAL, whereas AML exerted a significantly stronger effect during the last 4 h of the dosing interval – possibly influencing the differences in office BP found in the main study. Mean heart rate (HR) was higher on AML (72.3 bpm) than on VAL (70.5 bpm) (P = 0.013), suggesting a sustained difference in sympathetic activation. Correlation analysis showed a close relationship between treated ABP levels and the occurrence of combined cardiovascular endpoints – superior to the relationship to office BP. Conclusions In these elderly high-risk patients, diastolic ABP levels tended to be less predictive than systolic, and daytime less predictive than night-time for all cardiovascular endpoints. The findings underline the importance of ABP substudies in comparative trials for elucidating significant differences in pharmacodynamics, and stresses the superior predictive power of ABP.

Cholesterol reduction following health screening in general practice.

Objectives - To evaluate changes in plasma cholesterol following health screening and health discussions in general practice. Design - Randomised prospective population-based study conducted over a period of 5 years. Setting - Primary care, all general practitioners (GPs) in a welldefined area. Subjects - A random sample of inhabitants aged 30-49 years in January 1991, registered with a local GP was invited to participate. The participants (1507 persons, or 75.4% of the 2000 invited) were randomly allocated to two intervention groups and a control group. Main outcome measures - Plasma cholesterol, percentage of subjects with plasma cholesterol higher than 7 mmol/l. Results - After 5 years of intervention, plasma cholesterol in the whole population was significantly lower in the intervention groups compared to the control group. The decrease was most pronounced (0.5 mmol/l) in subjects at high cardiovascular risk. The percentage of high-risk individuals with a cholesterol level higher than 7 mmol/l was significantly lower in the intervention groups compared to the control group (9.8% vs 6.2%, p =0.04), corresponding to a 37% reduction. Conclusions - The study shows that the health checks had a measurable impact on plasma cholesterol levels, the most pronounced effect is seen among individuals at high cardiovascular risk.

Incidence of Bleeding in ‘Real-Life’ Acute Coronary Syndrome Patients Treated with Antithrombotic Therapy

Objective: Randomized clinical trials have reported low risks of bleeding in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients receiving triple antithrombotic treatment (aspirin, clopidogrel and heparin). As trial patients often differ substantially from unselected patients treated in routine clinical settings, we compared the incidence of bleeding in ‘real-life patients’ with the incidence in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial. Methods: We conducted a historical follow-up study based on 195 nonselected patients diagnosed with NSTE-ACS admitted to a Danish hospital. Data were obtained through systematic review of medical records. Bleeding complications were registered for 6 months after the event. Results: One hundred and nineteen (61.0%) patients fulfilled the inclusion and exclusion criteria of the CURE trial and were treated with triple antithrombotic therapy. Eleven (9.2%) of the 119 patients suffered a life-threatening bleeding. Their relative risk of life-threatening bleeding was 4.3 (95% CI 2.4–7.7) compared with the CURE study population. There was no difference in minor bleeding. Among patients not eligible according to the CURE criteria, but receiving intensive antithrombotic treatment, the relative risk of life-threatening bleeding was 6.4 (95% CI 3.1–12.9). Conclusions: When triple antithrombotic therapy is used in clinical practice in NSTE-ACS patients, the risk of bleeding may exceed that reported in trials. Assessment of the bleeding risk in the individual patient is warranted.

Effect of long-term remote ischaemic conditioning on platelet function and fibrinolysis in patients with chronic ischaemic heart failure

INTRODUCTIONnRemote ischaemic conditioning (RIC) protects against ischaemia-reperfusion injury through cellular protective pathways, but may also modulate haemostasis. We aimed to investigate the effect of long-term RIC on platelet function and fibrinolysis in patients with chronic ischaemic heart failure (CIHF).nnnMATERIAL AND METHODSnIn a prospective, outcome-assessor blinded, paired study, 16 patients with CIHF and 21 age- and gender-matched controls without ischaemic heart disease (IHD) were treated with RIC once daily for 28±4days. RIC was performed as four cycles of 5min upper arm ischaemia and reperfusion. We evaluated collagen and arachidonic acid induced platelet aggregation (Multiplate® Analyzer), platelet turnover (Sysmex® XE-5000), platelet activation (plasma soluble-platelet-selectin) and fibrinolysis (clot lysis time, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1)). We compared blood samples assessed at baseline and following long-term RIC.nnnRESULTSnLong-term RIC did not affect platelet aggregation, turnover or activation or PAI-1 in any study groups. Long-term RIC did not affect fibrin clot lysis time in patients with CIHF but reduced fibrin clot lysis time in matched controls without IHD (median: 773s (interquartile range: 689-936) vs. 658s (618-823), p=0.03). t-PA was increased following long-term RIC in CIHF patients (2.5 (1.7-3.4) vs. 2.9 (1.8-4.0), p=0.03) and in matched controls without IHD (1.5 (1.3-1.9) vs. 1.6 (1.4-2.3), p=0.03).nnnCONCLUSIONSnWhile long-term RIC did not affect collagen or arachidonic acid induced platelet aggregation, platelet turnover or sP-selectin, fibrinolysis was increased although most consistently in matched controls without IHD. This finding suggests that RIC may stimulate fibrinolysis potentially reducing the risk of thrombosis.

Effect of long-term remote ischemic conditioning in patients with chronic ischemic heart failure

Remote ischemic conditioning (RIC) protects against acute ischemia–reperfusion injury and may also have beneficial effects in patients with stable cardiovascular disease. We investigated the effect of long-term RIC treatment in patients with chronic ischaemic heart failure (CIHF). In a parallel group study, 22 patients with compensated CIHF and 21 matched control subjects without heart failure or ischemic heart disease were evaluated by cardiac magnetic resonance imaging, cardiopulmonary exercise testing, skeletal muscle function testing, blood pressure measurement and blood sampling before and after 28xa0±xa04xa0days of once daily RIC treatment. RIC was conducted as four cycles of 5xa0min upper arm ischemia followed by 5xa0min of reperfusion. RIC did not affect left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) in patients with CIHF (pxa0=xa00.63 and pxa0=xa00.11) or matched controls (pxa0=xa00.32 and pxa0=xa00.20). RIC improved GLS in the subgroup of patients with CIHF and with NT-proBNP plasma levels above the geometric mean of 372xa0ng/l (pxa0=xa00.04). RIC did not affect peak workload or oxygen uptake in either patients with CIHF (pxa0=xa00.26 and pxa0=xa00.59) or matched controls (pxa0=xa00.61 and pxa0=xa00.10). However, RIC improved skeletal muscle power in both groups (pxa0=xa00.02 for both). In patients with CIHF, RIC lowered systolic blood pressure (pxa0<xa00.01) and reduced NT-proBNP plasma levels (pxa0=xa00.02). Our findings suggest that long-term RIC treatment does not improve LVEF but increases skeletal muscle function and reduces blood pressure and NT-proBNP in patients with compensated CIHF. This should be investigated in a randomized sham-controlled trial.

Cardiac rehabilitation after acute coronary syndrome comparing adherence and risk factor modification in a community-based shared care model versus hospital-based care in a randomised controlled trial with 12 months of follow-up.

Aim: To investigate whether phase II cardiac rehabilitation (CR) conducted by a community model of shared care CR (SC-CR) including health care centres and general practice was feasible and provided acceptable results and to compare SC-CR to hospital-based CR (H-CR) in a randomised controlled trial. Methods: Patients were randomised to H-CR or SC-CR after admission for acute coronary syndrome. In SC-CR, the general practitioner took over the responsibility of the remaining rehabilitation, pharmacological treatment and risk factor management after the initial visit to the hospital outpatient clinic. The Municipal Health Care Centres provided courses on smoking cessation, nutrition, and exercise training and contributed to disease education and psychosocial support. The main endpoint was adherence to the CR programme and compliance with lifestyle modifications. Results: In total, 1364 patients were screened, 327 (24%) were eligible, and 212 (65%) accepted participation. Phase II CR was completed by 192 (91%) of the participants. Full adherence to the CR programme was seen in 53% in SC-CR versus 54% in H-CR (relative risk (RR): 0.98, 95% confidence interval: 0.73–1.32). In H-CR, patients had higher rates of adherence to dietary advice and health education. In SC-CR, 12% of patients did not attend the risk factor evaluation and clinical assessment with their general practitioner. No difference in risk factor improvement was found. Exercise training was declined by 25% in both groups. Conclusion: Adherence to phase II CR was high in both groups. SC-CR did not improve adherence and efficacy, but had comparable effects on medication and risk factors. Thus, SC-CR was safe and effective.

Shared care versus hospital-based cardiac rehabilitation: a cost-utility analysis based on a randomised controlled trial

Background Changes in the organisation of chronic healthcare, an increased awareness of costs and challenges of low adherence in cardiac rehabilitation (CR) call for the exploration of more flexible CR programmes as alternatives to hospital-based CR (H-CR). A model of shared care cardiac rehabilitation (SC-CR) that included general practitioners and the municipality was developed. The aim of this study was to analyse the cost utility of SC-CR versus H-CR. Methods The cost-utility analysis was based on a randomised controlled trial of 212 patients who were allocated to SC-CR or H-CR and followed up for 12 months. A societal cost perspective was applied that included the cost of intervention, informal time, healthcare and productivity loss. Costing was based on a microcosting approach for the intervention and on national administrative registries for the other cost categories. Quality-adjusted life years (QALYs) were based on the EuroQol 5-Dimensions measurements at baseline, after 4 months and after 12 months. Conventional cost-effectiveness methodology was employed to estimate the net benefit of SC-CR. Results The average cost of SC-CR was 165.5 kDKK and H-CR 163 kDKK. Productivity loss comprised 74.1kDKK and 65.9 kDKK. SC-CR cost was an additional 2.5 kDKK (95%u2009CI −38.1 to 43.1) ≈ (0.33; −5.1 to 5.8 k€) and a QALY gain of 0.02 (95% CI −0.03 to 0.06). The probability that SC-CR would be cost-effective was 59% for a threshold value of willingness to pay of 300 kDKK (k€40.3). Conclusion CR after shared care model and H-CR are comparable and similar in socioeconomic terms. Trial registration number NCT 01522001; Results.