Heart Rate in Patients with Coronary Artery Disease - the Lower the Better? An Analysis from the Treating to New Targets (TNT) trial

Transcription

1 Heart Rate in Patients with Coronary Artery Disease - the Lower the Better? An Analysis from the Treating to New Targets (TNT) trial Sripal Bangalore, MD, MHA, Chuan-Chuan Wun, PhD, David A DeMicco, PharmD, Andrei Breazna, PhD, Prakash Deedwania, MD, Franz H Messerli, MD, on behalf of the TNT Steering Committee and Investigators New York University School of Medicine, New York, NY [SB] Pfizer, New York, NY [CCW, DAD, AB] University of California at San Francisco School of Medicine, Fresno, California [PD] St. Luke s-roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY [FHM]

2 Disclosure Information TNT trial was funded by Pfizer Inc. Sripal Bangalore: Advisory board- Daiichi Sankyo Chuan-Chuan Wun: Pfizer employee David A DeMicco: Pfizer employee Andrei Breazna: Pfizer employee Prakash Deedwania: None Franz H. Messerli: Consulting: Abbott, Novartis, Pfizer, Bayer, Forest, Daiichi-Sankyo, Sanofi, Medtronics and received research/grants from Servier, Forest, and Novartis,

3 Background You only get so many heartbeats... Samuel A. Levine, MD ( ) Cook et al. Eur Heart J. 26 Oct;27(2):

4 Post Myocardial Infarction In patients presenting with ACS, a reduction in heart rate (HR) of at least 15 beats/min during infarct evolution is associated with a reduction of infarct size between 25-3% Kjekshus et al. Am J Cardiol 1986;57:43F-9F

5 Post MI: HR and Re-infarction Kjekshus et al. Am J Cardiol 1986;57:43F-9F

6 Background In patients with coronary artery disease, a direct linear relationship has been shown between lower heart rate and improved longterm cardiovascular prognosis However, the data are limited and the cardiovascular prognosis at very low heart rates has not been fully explored

7 In-hospital death, non-fatal MI or stroke In-hospital death Bangalore et al. Eur Heart J. 21;31(5):552-56

8 PROVE-IT TIMI 22 Trial Bangalore et al. J Am Coll Cardiol. 21;55 (1A): A98.E924

9 Objectives To evaluate the relationship between achieved resting heart rate as a predictor of long-term cardiovascular events in patients with CAD enrolled in the Treating to New Targets (TNT) trial

10 TNT Trial 1,1 patients with stable coronary heart disease Age years, LDL between 13 and 25 mg/dl Atorvastatin 8 mg n=4,995 Atorvastatin 1 mg n=5,6 Primary Endpoint: Major cardiovascular event defined as death from coronary disease, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke at a median follow-up of 4.9 years

11 Methods: Follow-up Patients were followed up at Week 12 and at Months 6, 9, and 12 during the first year and then every 6 months thereafter At each visit, vital signs, clinical end points, adverse events, and concurrent medication information were collected HR management was at the discretion of the treating physician For this analysis, the average follow-up HR were calculated for each patient by using all follow-up values, up to the last visit prior to the date of primary outcome or end of follow-up in those without events

12 Study Outcomes Primary outcome: Composite of death from coronary heart disease (CHD), non-fatal, nonprocedure-related MI, resuscitation after cardiac arrest, or fatal or non-fatal stroke Secondary outcomes: Individual outcomes of allcause mortality, CV mortality, nonfatal MI or stroke

13 Statistical Analyses HR values were categorized as 1 bpm increments for association with clinical outcomes Three models were tested: Model 1: Multivariable non-linear Cox proportional hazard analysis was performed including HR category as the major factor adjusting for baseline variables and treatment effect Model 2: Multivariable non-linear Cox proportional hazard analysis using HR as a time dependent variable Model 3: Multivariable Cox regression with restricted cubic splines including heart rate as a time-dependent covariate with three knots at 35, 55, and 75 bpm Nadir HR was calculated based on Delta method, which is equal to the coefficient of linear term divided by 2 * coefficient of quadratic term

14 Results: Baseline Characteristics Parameter < 5 bpm (n = 716) 5 - <6 bpm (n = 3465) 6 - < 7 bpm (n = 3514) 7-8 bpm (n = 1473) > 8 bpm (n = 434) p- value a Age (years) 61.9 ± ± ± ± ± Men, n (%) 625 (87.3%) 2889 (83.4%) 2823 (8.3%) 1125 (76.4%) 328 (75.6%) <.1 Body Mass Index ( kg/m 2 ) ± ± ± ± ± 5.5 <.1 Never smoked, n (%) 196 (27.4%) 843 (24.3%) 826 (23.5%) 3 (2.4%) 85 (19.6%).1 Hypertension, n (%) 395 (55.2%) 1847 (53.3%) 1866 (53.1%) 834 (56.6%) 25 (57.6%).75 Diabetes, m (%) 63 (8.8%) 374 (1.8%) 531 (15.1%) 323 (21.9%) 131 (3.2%) <.1 Myocardial infarction, n (%) 439 (61.3%) 242 (58.9%) 1989 (56.6%) 843 (57.2%) 267 (61.5%).4 Coronary heart disease, n (%) 29 (4.1%) 152 (4.4%) 178 (5.1%) 92 (6.3%) 34 (7.8%).3 Peripheral vascular disease, n (%) 71 (9.9%) 383 (11.1%) 385 (11.%) 212 (14.4%) 72 (16.6%) <.1 Congestive heart failure, n (%) 33 (4.6%) 184 (5.3%) 275 (7.8%) 159 (1.8%) 72 (16.6%) <.1 Arrhythmia, n (%) 13 (18.2%) 69 (17.6%) 627 (17.8%) 28 (19.%) 18 (24.9%).5 Heart rate: Change from baseline to Final visit (bpm).46 ± ± ± ± ± <.1

15 Incidence of PO (%) Adjusted Hazard Ratio Heart Rate & Primary Outcome Model 1 Adjusted Hazard Ratio Nadir = 54.1 bpm <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm Primary outcome: Death from coronary heart disease (CHD), non-fatal, non-procedure-related MI, resuscitation after cardiac arrest, or fatal or non-fatal stroke

16 Adjusted Hazard Ratio Heart Rate & Primary Outcome Model 2 2,5 2 Adjusted Hazard Ratio Nadir = 51.6 bpm 1,5 1,5 <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm Primary outcome: Death from coronary heart disease (CHD), non-fatal, non-procedure-related MI, resuscitation after cardiac arrest, or fatal or non-fatal stroke

17 Heart Rate & Primary Outcome Model 3 Nadir = 51.6 bpm Primary outcome: Death from coronary heart disease (CHD), non-fatal, non-procedure-related MI, resuscitation after cardiac arrest, or fatal or non-fatal stroke

18 Incidence of Death (%) Adjusted Hazard Ratio 8 6 Heart Rate & CV Death Model 1 Adjusted Hazard Ratio Nadir = 37. bpm <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm

19 Adjusted Hazard Ratio Heart Rate & CV Death Model 2 2,5 2 1,5 1,5 <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm

20 Heart Rate & CV Death Model 3

21 Incidence of Death (%) Heart Rate & Non Fatal MI Model 1 Adjusted Hazard Ratio Adjusted Hazard Ratio Nadir = 57.7 bpm <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm

22 Adjusted Hazard Ratio 2,5 2 Heart Rate & Non Fatal MI Model 2 Nadir = 58.6 bpm 1,5 1,5 <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm

23 Heart Rate & Non Fatal MI Model 3 Nadir = 58.6 bpm

24 Incidence of Stroke (%) Adjusted Hazard Ratio 6 Heart Rate & Stroke Model 1 Adjusted Hazard Ratio 3 4 Nadir = 57.6 bpm <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm

25 Adjusted Hazard Ratio Heart Rate & Stroke Model 2 2,5 Nadir = 51.3 bpm 2 1,5 1,5 <5 5 to 59 6 to 69 7 to 8 > 8 Heart Rate, bpm

26 Heart Rate & Stroke Model 3 Nadir = 51.3 bpm

27 Limitations Post-hoc analysis that evaluated the relationship between HR and cardiovascular events in a CAD population with tight control of cholesterol levels and hence the results cannot be extrapolated to other populations We do not propose a causal relationship between low HR and risk of cardiovascular events We did not adjust our analyses for dosage of medications received

28 Conclusions In patients with CAD, the relationship between heart rate and the risk of future cardiovascular events follows a J-curve pattern. In contrast to the BP J-curve, there is no target organ heterogeneity with heart rate; the nadir for all outcomes is similar. Thus, lower is not always better for heart rate, and a target range of 5-59 bpm is optimal in patients with CAD.

29 Extra-Slides

30 Heart Block and Pacemaker use Parameter < 5 bpm (n = 716) 5 - <6 bpm (n = 3465) 6 - < 7 bpm (n = 3514) 7-8 bpm (n = 1473) > 8 bpm (n = 434) p- value a Heart block, n (%) (%) 3 (.9%) 12 (.34%) 4 (.27%) 3 (.69%).285* Pacemaker, n (%) 1 (.14%) 1 (.3%) 12 (.34%) 2 (.14%) 1 (.23%).413*

31 Incidence of Secondary Outcome (%) PROVE-IT TIMI 22 Trial: Secondary Outcome Adjusted Hazard Ratio 4 3 Adjusted Hazard Ratio Nadir = 7 bpm Total Patients < >=9 Heart Rate, bpm Secondary outcome: Death from CHD, nonfatal MI, or revascularization after 3 days

32 Incidence of Mortality (%) Adjusted Hazard Ratio PROVE-IT TIMI 22 Trial: All-Cause Mortality 12 9 Adjusted Hazard Ratio < >=9 Total Patients Heart Rate, bpm

33 PROVE-IT TIMI 22 Trial: Cardiovascular Mortality Incidence of Cardiovascular Mortality (%) Adjusted Hazard Ratio 6 Adjusted Hazard Ratio < >=9 Total Patients Heart Rate, bpm

34 Incidence of Non-Fatal MI (%) PROVE-IT TIMI 22 Trial: Non-Fatal MI Adjusted Hazard Ratio Adjusted Hazard Ratio Nadir = 65 bpm < >=9 Total Patients Heart Rate, bpm