Clinical Trials Update from the European Society of Cardiology Congress in Munich, 2008: TIME-CHF, CARESS-in-AMI, TRITON-TIMI 38, EUROPA, AF-CHF, and ADVANCE
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- Horowitz, J., Remme, W.J. & Torp-Pedersen, C. Cardiovasc Drugs Ther (2009) 23: 25. doi:10.1007/s10557-008-6153-4
Presented by H.P. Brunner-La Rocca from Basel, Switzerland
Background: The TIME-CHF study was designed to evaluate the potential utility of monitoring of plasma N-terminal brain natriuretic peptide (NT-BNP) levels as an adjunct to therapy for chronic heart failure in ageing individuals. The study addresses in particular the paucity of information about the relationship between manipulating of NT-BNP concentrations and outcomes in very elderly patients who constitute a substantial proportion of most chronic heart failure populations.
Methods: A prospective, single-blinded randomised single-centre study was conducted in 49 patients with symptomatic CHF, including related hospitalisation within the previous year. Randomisation, stratified according to patients’ age (60–74 vs 75 + years) was either to standard therapy or to an intensified regimen directed to reduce plasma NT-BNP concentrations, as a marker of improved CHF control. The primary end-point was hospitalisation-free survival.
Results: Patients entering the study had severe impairment of LV systolic function (mean LVEF approximately 30%) with considerably elevated NT-BNP concentrations (approximately 4,000 pg/ml) despite the majority being in NYHA Class II status at entry. The majority had severe comorbidities. In general, patients were extensively treated for CHF, and treatment was intensified during the study. The incidence of the primary end-point did not differ between treatment group. However, outcomes varied according to patients’ age with benefit of intensified therapy only in patients <75 years old at entry.
Conclusions: This study failed to identify clear cut benefit resulting from a strategy of uptitrating CHF therapy in order to reduce NT-BNP levels. However, it is likely that some benefit occurred in “younger” individuals. The failure to relate NT-BNP reduction to outcome improvement in older patients may indicate that prevention of ventricular distension is of less importance in control of CHF symptoms in such individuals.
2 CARESS-in-AMI 1 year outcomes
Presented by K.Z. Zmudka from Krakow, Poland
Background: The CARESS-in-AMI trial was set up to test the hypothesis that a high-risk subset of patients undergoing thrombolytic therapy for evolving STEMI may benefit further from immediate transfer for PCI.
The previously published results of the study relate to 30-day outcomes. High-risk characteristics in the 600 patients studied, all aged <75 years, included extensive S-T elevation, left ventricular ejection fraction ≤35%, pulmonary congestive changes, previous infarction and/or new-onset left bundle branch block. Importantly, patients randomised to thrombolysis/transfer initially received half-dose reteplase, abciximab plus heparin. Patients randomised to thrombolysis only were eligible for “rescue” PCI in case of persistent S-T elevation or clinical deterioration.
Early Results: The primary endpoint of the study, a composite of death, reinfarction and refractory ischaemia within 30 days, occurred in 4.4% of the PCI group and 10.7% of the standard care group (p < 0.01), without a significant increased in major bleeding.
One year follow up: At this stage, the primary endpoint had occurred, 11.4% of patients in the PCI group and 16.4% within the standard care group (p = 0.07). However, there was a persistently lower incidence of refractory ischaemia in the PCI group (3.4 vs 8.7%l p < 0.01). Mortality rates were virtually identical.
Conclusions: The 1-year follow up data suggest some attenuation of the early benefit of a “pharmaco-invasive” approach. Furthermore, despite the selection of patients with high-risk clinical features in CARESS-in-AMI, it is clear that the major benefits of an early transfer strategy do not include any substantial reductions in mortality, but rather circumvention of late ischaemia.
3 PRASUGREL vs CLOPIDOGREL in patients with STEMI undergoing PCI (sub-set of the TRITON-TIMI 38 study)
Presented by G. Montalescot from Paris, France
Background: In the TRITON-TIMI 38 trial, prasugrel was compared to clopidogrel in 13,608 patients with acute coronary syndromes, of whom 74% had unstable angina/non Q-wave infarction and 24% had STEMI. All patients underwent urgent PCI.
The primary efficacy end-point of the study (an agglomerate of cardiovascular death, myocardial infarction and non-fatal stroke) occurred in 9.9% of patients receiving prasugrel and 12.1% of those receiving clopidogrel (p < 0.001). Rates of late stent thrombosis were halved with prasugrel therapy. However, major bleeding was significantly increased in the prasugrel group (2.4 vs 1.8%; p < 0.05).
Further Results: Data related to the 3,534 STEMI patients in the TRITON-TIMI 38 study were presented. These patients were generally younger than those with non-Q-wave AMI, with fewer comorbidities.
At a mean of 450 days’ follow-up, the primary end-point had occurred in 10% vs 12.4% of patients, a similar risk reduction to that in the entire study population. Stent thrombosis rates at 450 days were 1.6 vs 2.8% (p < 0.05). Surprisingly, however, there was no excess of major haemorrhage for prasugrel therapy in this population.
Discussion: The data confirm that the overall beneficial effects of prasugrel, compared to clopidogrel, apply within the STEMI subset of the TRITON-TIMI 38 patient population . The lack of an excess of haemorrhagic complications in this subset is reassuring, but the basis for the finding is uncertain, and Type II error cannot be excluded. Furthermore, the results of the STEMI subset reinforce the argument that more intensive, but predictable, anti-aggregatory effects of prasugrel may translate to long-term improvement in patient outcomes.
4 Prognostic value of resting heart rate in stable CAD patients—results from EUROPA
Presented by R. Ferrari from Ferrara, Italy
Background: Heart rate is an independent predictor of all-cause and cardiovascular mortality in the general population as well as in patients with coronary artery disease (CAD) and left ventricular dysfunction or hypertension. In the CASS registry consisting of 24,913 patients with CAD a heart rate of ≥83 beats/minute (bpm) was associated with significantly more overall death and cardiovascular mortality, compared to patients with a heart rate ≤62 bpm . In that study survival was inversely related to left ventricular function
Similarly, in INVEST (22,576 patients) a heart rate of ≥75 bpm was associated with more cardiovascular events in patients with CAD and hypertension .
However, there are currently no data on the prognostic role of heart rate in CAD patients without heart failure on optimal preventive therapy. The EUROPA study offered the opportunity to gain better insight of the role of heart rate in such a population.
In EUROPA 12,218 patients with stable, documented CAD without heart failure were randomised to perindopril 8 mg daily or matching placebo, and followed up for 4.2 years. This resulted in 51,300 patient years for analysis .
The primary endpoint of the EUROPA study (cardiovascular death, non-fatal myocardial infarction and resuscitated cardiac arrest) was significantly improved by 20% RRR in favour of perindopril .
The current presentation concerned a retrospective analysis of the effect of baseline heart rate on cardiovascular outcomes in two groups: those with a heart rate <75 bpm and those with a heart rate of ≥75 bpm. A Cox proportional hazards model was used to adjust for possible confounding factors.
The <75 bpm group consisted of 9,071 patients while 3,134 patients were in the higher heart rate group. There were significant baseline differences. The higher heart rate group consisted percent-wise of less males, higher cholesterol, BMI and blood pressure levels. Also, more in this group had a history of hypertension, diabetes and smoking. In contrast, more patients in the lower heart rate group were treated with beta-blockers, lipid-lowering drugs and antiplatelet agents.
After adjustment for these differences as well as for allocation to perindopril or placebo, the patients with a heart rate ≥75 bpm had a greater risk of dying compared to lower heart rate patients (relative risk 21% at the end of the study, p < 0.05)). Likewise, there was a 24% greater risk of cardiovascular death (p < 0.05) and of 51% for hospitalisations for heart failure (p = 0.013) in the high heart rate group. Also, the combined endpoint of hospitalisation for heart failure and /or cardiovascular mortality was significantly increased by 23% (p = 0.025)
No significant differences were observed in fatal or non-fatal myocardial infarctions.
The authors concluded that in stable CAD patients without heart failure on optimal preventive therapy an elevated heart rate ≥75 bpm is an independent predictor of total and cardiovascular mortality and hospitalisation for heart failure.
Perspective: this analysis indicates that heart rate may be considered in the risk stratification of patients with CAD, not only those with heart failure, LV dysfunction (a previous analysis of EUROPA indicated that >90% of the patients in that study had a normal left ventricular function) or hypertension.
This is important now it is possible to selectively reduce heart rate with If blocking agents such as ivabradine. Whereas a large trial in patients with heart failure (SHIFT) is ongoing, further prospective studies of the role of this agent in patients with stable CAD without heart failure or LV dysfunction, i.e. the EUROPA patient are warranted to extend currently available secondary preventive actions in this patient population.
5 Synergistic effect of perindopril and calcium channel blockers in prevention of cardiac events and death in coronary artery disease
Presented by M. Bertrand from Lille, France
Background: In the EUROPA study, perindopril significantly reduced cardiovascular death, non-fatal myocardial infarction and resuscitated cardiac arrest by 20% in 12,218 patients with stable CAD, compared to placebo. In the ASCOT study, the combination of perindopril and amlodipine resulted in a 24% RRR of cardiovascular mortality in 19,257 hypertensive patients at risk of cardiovascular events when compared to a strategy of atenolol combined with thiazides . The latter study may suggest that a combination of perindopril and a calcium channel antagonist might lead to a further benefit in stable CAD patients over an above the use of perindopril alone.
The objective of the analysis presented here was to study the effect of the ACE inhibitor perindopril compared with placebo in patients with stable CAD receiving calcium channel blockers (CCB) on the risk reduction in major cardiac events and death.
Secondly, to assess the synergistic effects between perindopril and CCB.
In the patients randomised to perindopril (n = 6,110), 1,022 were on CCB therapy throughout the study, and 1,100 in the placebo group (n = 6,108).
Synergy was considered when the Hazard Ratio (HR) in the perindopril + CCB group (determined as HR [perindopril + CCB vs placebo + CCB]) was lower than the HR perindopril alone (determined as HR[perindopril-CCB vs placebo-CCB]) × the HR CCB alone (determined as HR [placebo + CCB vs placebo-CCB]).
The primary endpoint was the same as that of the main study. Secondary endpoints included total mortality, cardiovascular mortality, fatal and non-fatal myocardial infarction and occurrence of new heart failure.
The baseline characteristics including medical history and medications were comparable between the groups perindopril + CCB and placebo + CCB.
The primary endpoint occurred significantly less in the perindopril + CCB (4.89 absolute risk) compared to placebo+CCB (7.45 absolute risk, p < 0.05). This resulted in a highly significant 35%RRR at the end of the study (95% CI: 0.45–0.92, p = 0.0147) in favour of the combination perindopril and CCB. Also, a 46% RRR was observed in the perindopril+CCB group relative to placebo + CCB (95%CI: 0.34–0.86, p < 0.01). There was a further tendency towards less CV mortality (HR 0.59, CI 0.32–1.08), all myocardial infarctions (HR 0.72, CI 0.45–1.07) and hospitalisations for heart failure (HR 0.46, CI 0.12–1./76).
The tests for synergy (adjusted for relevant baseline criteria including age, sex, previous myocardial infarction, PCI, CABG, peripheral vascular disease, hypertension, diabetes, and use of beta-blockers, nitrates and diuretics, and baseline blood pressure) indicated significant synergy of the combination of perindopril + CCB for all endpoints.
The authors concluded that the addition of an ACE inhibitor (perindopril) to a calcium channel blocker in stable patients with coronary artery disease significantly reduces the risk of total mortality and a composite endpoint of cardiovascular death, non-fatal myocardial infarction and resuscitated cardiac arrest. The clinical interaction between perindopril and CCB suggests a synergistic effect which should be further investigated
The study results are interesting. However, as this is a post-hoc analysis there is a clear need for further evaluation in a prospective design in larger patient populations.
A further, but less important concern is that the type CCB was not registered in the EUROPA study. It is likely, though, that the CCB used in the majority were of the dihydropyridine derivative type as heart rates were not different between groups taking a CCB and those who did not.
6 Atrial Fibrillation and Congestive Heart Failure (AF-CHF) Trial
Presented by Roy Denis from Montreal, Canada
Background: Atrial fibrillation (AF) is associated with worse outcome in patients with heart failure (HF). Strategies to restore and maintain sinus rhythm are believed beneficial, but these potential benefits have not been adequately studied in large controlled trials. As patients with heart failure may have an increased risk of adverse events with anti-arrhythmic therapy, rate control may be an alternative. The AF-CHF study was designed to compare the effect of rhythm versus rate control on cardiovascular mortality in patients with heart failure and atrial fibrillation.
Methods: Patients with a left ventricular ejection fraction ≤35% and a history of HF NYHA class II–IV during the last 6 months, or an asymptomatic condition leading to hospitalisation for HF during the last 6 months or left ventricular ejection fraction ≤25%, and documented AF lasting for ≥6 h, or requiring cardioversion within the preceding 6 months, or an episode lasting at least 10 min during the last 6 months and previous cardioversion for AF, and eligibility for long term treatment, were included. The primary endpoint was death from cardiovascular causes. Secondary endpoints included all-cause mortality, worsening heart failure, hospitalisations, quality of life, cost of therapy and a composite of cardiovascular death, stroke or worsening heart failure.
The main outcomes have been published recently . One thousand three hundred seventy-six patients were randomised the rhythm control group (anti-arrhythmic therapy with amiodarone and cardioversion if not successful, n = 682) or the rate-control group (beta-blockade with digitalis, n = 694). Over a follow-up period of 37 months there was no difference in primary and secondary endpoints between both treatment groups.
At the Trial Update Session of the ESC congress the results were disclosed for changes in NYHA class, 6 min walking test and Quality of Life measurements.
For each of these measures there was a significant improvement in the whole patient population during the trial, but there was no difference or even a trend towards difference between rate control and rhythm control.
Although the study is important in the sense that it confirms in a large population with HF and atrial fibrillation that rhythm control is not superior to rate control, there are several concerns with the study. These include a high cross-over rate between study groups and sub-optimal control of sinus rhythm in the rhythm control group (about 65% had at least one recurrent episode of atrial fibrillation. Moreover, about 60% in the rate-control group had persistent atrial fibrillation. Also, the use of beta-blockade to control heart rate may well have had an independent beneficial effect on outcomes.
Nevertheless, as suggested by the discussant at the ESC presentation, Aldo Maggione, the results of the AF-CHF study should be considered a first-choice approach in patients with heart failure and atrial fibrillation, and rhythm control considered in patients with persisting symptoms.
7 Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation—results of the ADVANCE study
Presented by A. Patel from Sydney, Australia
The ADVANCE study evaluated whether among patients with diabetes routine blood pressure powering prevents major vascular events, whether similar benefits would be observed in hypertensive versus non-hypertensive patients, and whether this would add to the benefits produced by other cardiovascular preventive therapies, including ACE inhibitors. The main study results have been published . The current presentation concerned patients with atrial fibrillation and diabetes. More specifically the question whether in these patients atrial fibrillation is an independent marker of vascular risk and what the effect of routine blood pressure lowering is in these patients.
The ADVANCE study randomised 11,140 patients with type 2 diabetes, 55 years or older, and with additional risk of a vascular event. This could be age ≥65 years, history of macro- or microvascular disease, a first diagnosis of diabetes >10 years prior to study entry, or ant other major risk factor. 5,569 patients were assigned double-blind to perindopril/indapamide combination (2.0/0.625 mg first 3 months, followed by 4.0/1.25 mg thereafter) or matching placebo (5,571 patients), but could receive additional blood pressure lowering therapy or open-label perindopril (≤4 mg daily) at the discretion of the treating physician.
Of the total population, 847(7.6%) patients had atrial fibrillation at baseline. Patients with atrial fibrillation were slightly older, had a higher blood pressure, worse renal function, more history of macrovascular disease and were more often treated for hypertension. 26% were on anticoagulant therapy versus 2% in the non-atrial fibrillation group.
Atrial fibrillation was associated with a substantial increased risk of cerebro-vascular accidents (HR 1.70; 95% confidence intervals:1.27–2.27, p < 0.0001), adjusted for relevant baseline criteria. It also significantly increased the risk of all-cause death (HR 1.71 (95% CI: 1.4–2.08), cardiovascular death (HR 1.92; 95% CI: 1.49–2.48), major coronary events (HR 1.35 (95% CI: 1.03–1.76) and heart failure (HR 1.96: 95% CI: 1.5–2.57).
Whereas the main ADVANCE study found a significant 14% relative risk reduction in mortality, this sub-analysis in patients with atrial fibrillation found no interaction and the same relative effect of treatment in patients with atrial fibrillation. Also, there was no evidence of heterogeneity in treatment effect by baseline anticoagulant use. Consequent to the increased risk with atrial fibrillation, significantly less number of patients with atrial fibrillation would be needed to treat to avoid one all-cause death and, particularly, one cardiovascular death.
The conclusion of this sub-study was that atrial fibrillation is an important risk factor among patients with type 2 diabetes and that prophylactic treatment with perindopril/indapamide is important in these patients.