Updates in hypertension management what to expect from jnc 8
Van Gelder Race
1. RACE II RA te C ontrol E fficacy in Permanent Atrial Fibrillation A Randomized Comparison of Lenient Rate Control versus Strict Rate Control Concerning Morbidity and Mortality Isabelle C Van Gelder, Hessel F Groenveld, Harry J Crijns, Jan G Tijssen, Hans H Hillege, Ype Tuininga, Marco Alings, Hans Bosker, Jan Cornel, Raymond Tukkie, Otto Kamp, Dirk J Van Veldhuisen, Maarten P Van den Berg, on behalf of the RACE II Investigators
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5. Hypothesis Lenient rate control is not inferior to strict rate control in patients with permanent AF in terms of cardiovascular morbidity and mortality
11. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG)
12. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG)
13. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG) HR < 80 bpm (12 lead ECG) and HR < 110 bpm (at 25% duration of maximal exercise time)
14. Permanent AF > 80 bpm lenient strict HR < 110 bpm (12 lead ECG) HR < 80 bpm (12 lead ECG) and HR < 110 bpm (at 25% duration of maximal exercise time) After achieving rate control target: Holter for safety
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17. Noninferiority boundary is 10% absolute difference* Statistical hypotheses H o : R lenient - R strict > 10% (inferiority) H 1 : R lenient - R strict < 10% (non-inferiority) The null hypothesis of inferiority will be rejected when the upper limit of the 2-sided 90%-confidence interval of the risk difference does not exceed 10%. Statistical analysis * Comparable to the noninferiority boundary in the first RACE trial
18. Baseline characteristics Lenient control Strict control n= 311 n=303 Age 69±8 67±9 Male 66% 65% Duration AF Total duration 16 (6-54) 20 (6-64) months Permanent AF 3 (1-6) 2 (1-5) months
21. Rate control targets at end of dose-adjustment phase Lenient control Strict control n= 311 n=303 Rate control target 98% 67%* Resting target 98% 75% Exercise target - 73% Visits to achieve target 0.2 ±0.6 2.3±1.4* Median 0 2* Interquartile range 0-0 1-3 * P<0.001
22. Lenient control Strict control n= 311 n=303 None 10% 1%* Beta-blocker alone 42% 20%* Calcium blocker alone 6% 5% Digoxin alone 7% 2%* Beta-blocker + calciumblocker 4% 13%* Beta-blocker + digoxin 19% 37%* Calciumblocker + digoxin 6% 10% Beta + calciumblocker + digoxin 1% 9%* Rate control medication at end of dose-adjustment phase * P<0.01 30% 69%*
23. Lenient control Strict control n= 311 n=303 Beta-blocker (normalized to metoprolol-equivalent doses) 120±78 162±85 mg* Verapamil 166±60 217±97 mg* Digoxin 0.19±0.8 0.21±0.8 mg Rate control doses at end of dose-adjustment phase * P<0.001
24. Heart rate during study * * P<0.001 * * * No. At Risk Lenient 311 311 302 291 237 Strict 303 303 284 277 240 Lenient Strict months Heart rate (beats per minute)
29. 3-y incidence Lenient control Strict control All patients 12.9% 14.9% CHADS 2 < 2 12.4% 9.6%* CHADS 2 ≥ 2 13.6% 25.0%** Inferiority hypothesis rejected for both subgroups (*p=0.02 and **p<0.001) Primary outcome
30. Symptoms Lenient Strict Lenient Strict % Symptoms Palpitations Fatigue Dyspnea baseline end of study
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33. Van Gelder,Groenveld,Van Veldhuisen, Van den Berg University Medical Center Groningen Janssen, Tukkie Kennemer Hospital Haarlem Bendermacher, Olthof Elkerliek Hospital Helmond Robles de Medina Hospital Leyenburg The Hague Kuijer, Zwart Hospital Bernhoven Oss Crijns Maastricht University Medical Center Alings Amphia Hospital Breda Post Hospital Hengelo Peters, Van Stralen, Buys Hospital Gooi Noord Blaricum Dani ë ls Jeroen Bosch Hospital Den Bosch Timmermans Medical Spectrum Twente Enschede Kuijper, Van Doorn Spaarne Hospital Hoofddorp Hoogslag Diaconessen Hospital Meppel Den Hartog Hospital Gelderse Vallei Ede Van Rugge Diaconessen Hospital Leiden Derksen, Bosker Rijnstate Hospital Arnhem Hamraoui Tweesteden Hospital Tilburg De Milliano Hospital Hilversum Kamp VU Medical Center Amsterdam Kragten Atrium Medical Center Heerlen Linssen Twenteborg Hospital Almelo Tuininga, Badings Deventer Hospital Deventer Nierop St. Franciscus Hospital Rotterdam Gratama VieCurie Hospital Venlo Nio, Muys, Van den Berg IJsselland Hospital, Capelle aan de IJssel Thijssen Maxima Medical Center Veldhoven Van Dijkman Bronovo Hospital The Hague Cornel Medical Center Alkmaar Van der Gali ën St.Lucas Hospital Winschoten Boersma St.Antonius ospital Nieuwegein Bronzwaer Zaans Medical Center De Heel Zaandam Spanjaard Delfzicht Hospital Delfzijl Bartels Martini Hospital Groningen
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35. This article is now available on the New England Journal of Medicine’s website, NEJM.org
39. Symptoms Lenient control Strict control At baseline 56% 58% Palpitations 20% 27% Dyspnea 34% 37% Fatigue 28% 32% At end of study 46% 46% Palpitations 11% 10% Dyspnea 30% 30% Fatigue 24% 23%
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41. Primary outcome according to HR at end dose adjustment phase Lenient control Strict control % (events/total pts) Total group 12.9 (38/311) 14.9 (43/303) Heart rate < 70 - (1/1) 20.4 (13/67) Heart rate 70-80 20.0 (1/5) 11.7 (18/161) Heart rate 81-90 15.0 (16/112) 10.7 (4/39) Heart rate 91-100 9.1 (11/123) 5.6 (1/20) Heart rate > 100 14.1(9/70) 46.4 (7/16)
42. Lenient control Strict control % (events/total pts) Total group 12.9 (38/311) 14.9 (43/303) Heart rate < 70 - (1/1) 20.4 (13/67) Heart rate 70-80 20.0 (1/5) 11.7 (18/161) Heart rate 81-90 15.0 (16/112) 10.7 (4/39) Heart rate 91-100 9.1 (11/123) 5.6 (1/20) Heart rate > 100 14.1(9/70) 46.4 (7/16) Heart rate d at end of dose adjustment phase
Mr chairmen ladies and gentlemen It is my pleasure to present to you the results of the RACE II study, that is Rate control efficacy in permanent atrial fibrillation, a randomized comparison of lenient versus strict rate control concerning morbidity and mortality, carrying the acronym RACE II
AFFIRM and RACE showed that rates of complications and death were similar in patients treated with rate control and rhythm control therapy Since then rate control has become front-line therapy in the management of AF The optimal level of heart rate control during AF, however, is still unknown
The present guidelines advocate a strict rate control approach with control of heart rate at rest between 60 and 80 and at moderate exercise between 90 and 115 beats per minute However, these guidelines are not evidence based
But even if strict rate control is the standard of care today, It is difficult to achieve There is a higher chance on adverse effects of rate control drugs leading to more pacemaker implants And associated with higher costs Pro weglaten, beginnen met conThis slide shows the arguments pro and con strict rate control wer strokes (en fewer bleeding) nog uitleggen via lower chads2score omdat minder hartfalen en ook vanwege fewer drugs and therefore less INR instability irregular HR still present?? Is dat een verschil waar je op wil wijzen? M.a.w. waarom zou je strict doen als HF toch irregulr blijft? OK ….
Therefore it was our hypothesis that Lenient rate control is not inferior to strict rate control in patients with permanent AF in terms of cardiovascular morbidity and mortality
The RACE II trial is A prospective randomized open trial with blinded endpoint evaluation is a multicenter noninferiority trial With a follow of 2 to 3 years
Inclusion criteria were Permanent atrial fibrillation with a duration of a maximum of 12 months A resting heart rate above 80 beats per minute Patients had to be on oral anticoagulation And have a maximal age of 80 years
We excluded patients who satisfied any of these exclusion criteria: Paroxysmal or transient atrial fibrillation Known contra indications for either strict or lenient rate control, e.g.previous adverse effects on rate control drugs Unstable heart failure Cardiac surgery during the last 3 months Previous stroke Current or foreseen pacemaker, ICD or CRT therapy Inability to walk or bike
Patients were randomized to lenient or strict rate control
Patients randomized to lenient rate control
Were treated with rate control drugs aiming at a RESTING heart rate below 110 beats per minute
Patients randomized to strict rate control
Were treated with negative dromotropic drugs in order to achieve 2 targets: a resting heart rate below 80 beats per minute, and a heart rate during moderate exercise, which was defined as the heart rate at 25% duration of the maximal exercise time, below 110 beats per minute
a Holter was performed for safety
To achieve the targets patients were treated with negative dromotropic drugs, being beta-blockers, non dihydropyidine calcium channel blockers and digoxin, alone or in combination Dosages of drugs were increased or drugs combined until the heart rate target or targets in the strict control group were achieved
Primary outcome was a composite of Cardiovascular mortality Hospitalization for heart failure necessitating start or dose increase of treatment with diuretics And hence stroke, systemic emboli, major bleeding Syncope, sustained ventricular arrhythmia and cardiac arrest Life threatening adverse effects of rate control drugs PM implantation for bradycardia and ICD implantation for ventricular arrhythmias, thus not if part of regular treatment
The aim of the study was to show that lenient rate control is not inferior to strict rate control Therefore the statistical approach was that of testing for noninferiority. The noninferiority boundary was set at 10 percentage point absolute difference, comparable to the noninferiority boundary in the first RACE trial. The null hypothesis of inferiority will be rejected when the upper limit of the 2-sided 90% confidence interval of the risk difference between lenient and strict rate control does not exceed 10% The null hypothesis was that the risk of an endpoint event under lenient rate control minus the risk under strict rate control was larger than 10%. In that case lenient rate control would be inferior to strict rate control. H0 en H1 H0 inferiority 0 hypothyss niet noemen H1 inferiority ndary of non inferiority is 10% Aim of the study is to reject the nil hypothesis. This means that the incidence of the primary endpoint in the rate control group must be <10% than the incidence on a primary endpoint in the rhythm control group.
we included 614 patients. The baseline profile was typical for an AF population 69 and 678 years of age, 66% males. Duration of permanent AF was 3 and 2 months in the lenient and strict group, respectively
the underlying cardiac conditions were also typical as is shown here Being predominantly hypertension but also coronary artery disease and valve disease. In this population only a few had lone AF. (There was one major imbalance 22% of the lenient and 15% of strict control patients had coronary artery disease.)
We included relatively low risk patients, mean CHADS2 score was 1.4. The majority of patients had a score of zero or 1, 13% and 14% had a score of 3 or more.
At the end of the dose adjustment phase the rate control target was achieved in 98% of the patients randomized to lenient rate control versus 67% in the patients randomized to strict rate control. Also the number of visits necessary to achieve the heart rate target was lower in the lenient group, 0.2 versus 2.3 visits.
Rate control medication at the end of dose adjustment phase was used more intensive in the strict RC patients. - 10% of the pts in the lenient group did not need any medication against 1% if the strict group. 69% needed a combination of 2 or 3 RC drugs versus 30% in the lenient group and beta-blockers alone sufficed in 42% in the lenient pts versus 20% in the strict group.
At the end of dose adjustment phase the doses of the drugs used were higher in the strict control group. 160 against 120, 217 against 166 milligrams
Achieved heart rates were substantially different between the treatment groups. During the titration phase pts in the strict group went down from 96 to 75 bpm whereas in the lenient there was a reduction from 96 to 93 bpm. Thereafter the differences remained constant.
This slide shows the KM curves in the strict and lenient group over 3 years of follow up. The 2 Kaplan-Meijer curves were superimposible with a slight trend favoring lenient control with a cumulative incidence of the primary outcome of 12.9% for the lenient and 14.9% for the strict group.
The difference between the lenient and strict group was minus 2.0 % With a 90% confidence interval ranging from -7.6 to plus 3.5% The upper limit was way below the boundary for nonferiority of 10% Which means that the inferiority hypothesis was rejected, with a p value for noninferiority of less than 0.001 12.9 en 14.9 hier niet meer herhalen
this slide shows the distribution of morbidity and mortality over the various components of the primary endpoint adds up to 16,8% and 20,3% CV mortality was seen in 2.9% and 3.9% in lenient and strict group, respectively. HF occurred in 3.8 and 4.1%, stroke in 1.6 and 3.9%, systemic embolism in 0.3% n the lenient group, and bleeding in 5.3 and 4.5%. Adverse effects of rate control drugs in 1.1% versus 0.7% in the lenient and strict group, pacemakers in 0.8% in the lenient group versus 1.4% in the strict group. Syncope and ICD implantation were also low in both groups. No double counts within lines between lines double counts are possible The individual components of the primary outcome were also not significantly different.
this slide shows the split of the primary outcome in terms of fatal and non fatal events. Non fatal events occurred in 10% in the lenient group and in 11% in the strict group. fatal cardiovascular events occurred in 2.9% in the lenient versus 3.9% in the strict group, 9 and 11 patients respectively. Cardiovascular mortality was predominantly of noncardiac vascular origin, rather than due to lethal arrhythmias or heart failure
Subanalysis shows that the primary outcome event in patients with a CHADS 2 below 2 occurred in 12.4 in the lenient and 9.6% in the strict group. In patients with a high CHADS 2 score, i.e. high risk patients the difference was more outspoken 13.6 versus 25%. For both subgroups the inferior hypothesis could be rejected, indicating that lenient was noninferior to strict rate control in low and high risk patients
No differences were observed in symptoms associated with AF between both groups, at baseline and end of study. At end of study the was a small decline in both group, predominantly due to a reduction of palpitations from 20 and 27% in the lenient and strict group at baseline to 11% and 10% at end of study
we thank all the investigators in The Netherlands that contributed patients to the study
we also thank the DSMB, adjudication committee and finally we thank the people of the Trial Coordination Center in Groningen who took care of data collection and analysis the TCC
Finally, This article is now available on the NEJM’s website, NEJM.org I thank you for your attention
Heart rate during moderate exercise was assessed by using this figure provided after the exercise test. In this example, the patient exercised for a total of 8 minutes. At 25% of the total exercise duration, in this case 2 minutes
The heart rate was about 95 beats per minute, implying achievement of the exercise heart rate target in this patient. Thereafter, and in the strict group only
No differences were observed in symptoms associated with AF between both groups, at baseline and end of study. At end of study the was a small decline in both group, predominantly due to a reduction of palpitations from 20 and 27% in the lenient and strict group at baseline to 11% and 10% at end of study
Patients were seen every 2 weeks until the rate control target was achieved and after 1, 2 and 3 years of follow up.
Pro weglaten, beginnen met conThis slide shows the arguments pro and con strict rate control wer strokes (en fewer bleeding) nog uitleggen via lower chads2score omdat minder hartfalen en ook vanwege fewer drugs and therefore less INR instability irregular HR still present?? Is dat een verschil waar je op wil wijzen? M.a.w. waarom zou je strict doen als HF toch irregulr blijft? OK ….
Ik zou chads > 2 rechts in fuguur zetten en chads2 , 2 links; Getallen (%) in kolom centreren en niet tegen rand aanzetten
Heart rate during moderate exercise was assessed looking at this figure provided immediately after an exercise test. In this example, the patient exercised for a total of 13 minutes. At the 25% of the total exercise duration, in this case 3.25 minutes
The heart rate was about 130 beats per minute, thus in this patient the heart rate target was not achieved, and dose adjustment of negative dromotropic drugs or addition of another drug was done and repeated until the heart rate target eventually was achieved
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