Heart rate reduction as a goal in hypertension management

Transcription

1 Manage Hypertension Online Serono Symposia International Foundation (SSIF) Heart rate reduction as a goal in hypertension management Brian Tomlinson Professor of Medicine & Therapeutics Department of Medicine & Therapeutics The Chinese University of Hong Kong Prince of Wales Hospital Hong Kong SAR

2 Increased heart rate - Risk factor or risk marker? Increased heart rate Adapted from: Dzau V & Braunwald E.1991, and Bertrand M E, 2009.

3 Association of heart rate with cardiovascular events in population studies A Consensus Meeting of the European Society of Hypertension in 2005, identified 43 publications describing 39 population studies in the literature and all but two of these reported a significant association between fast heart rate and all-cause mortality in men 1 Some of the studies excluded deaths within the first two or more years of follow-up and found this did not alter the significant relationship 2,3 There have been several subsequent population studies which examined this relationship In some new studies, increased heart rate has been associated with increased cardiovascular risk in both men and women and has also been associated with increased risk of developing heart failure From: 1. Palatini P et al. J Hypertens 2006; 24(4): Gillman MW et al. Am Heart J. 1993; 125(4): Palatini P et al. Arch Intern Med. 1999; 159(6):

4 CHD mortality rate (per 1000 person years) CHD mortality rate (per 1000 person years) Elevated resting heart rate is an independent risk factor for cardiovascular disease National FINRISK Study Coronary heart disease mortality rates in each quintile of heart rate 6 Women n = 11,334 6 Men n = 10, < >82 Heart rate quintile 0 < >82 Heart rate quintile Elevated resting heart rate (RHR) showed a strong, graded, relationship with incident cardiovascular disease (CVD), which was stronger for fatal than nonfatal events Hazard ratios for CVD mortality for each 15 beats/min increase in RHR were 1.24 ( ) in men and 1.32 ( ) in women Relationship with coronary mortality was stronger and with total mortality was slightly weaker Independent of age, gender, total cholesterol, physical activity, systolic blood pressure, BMI, and HDL-C Adapted from: Cooney MT et al, Am Heart J 2010;159:612-9.

5 Adjusted Hazard Ratio for heart failure event Resting heart rate and incident heart failure in apparently healthy men and women: the EPIC-Norfolk study Multivariable adjusted hazard ratio for heart failure with 95% confidence interval (shaded area) in the total study population (n=20,048) In apparently healthy men and women aged yrs, during a mean followup of 12.9 yrs, each 10 beats/min increase in resting heart rate above the reference range (50-60 beats/min) was associated with an 11% increase in hazard of heart failure in multivariable analysis Resting Heart rate (beats/min) The results did not change materially after adjusting for myocardial infarction and coronary heart disease events during follow up Adapted from: Pfister R et al, Eur J Heart Fail 2012

6 Association of heart rate with cardiovascular events in hypertensive subjects baseline heart rate Some studies have examined the relationship between baseline resting heart rate and outcome in subjects with hypertension Gillman MW et al. Am Heart J 1993;125: Benetos A et al. Hypertension 1999;33:44-52 Farinaro E et al. Nutr Metab Cardiovasc Dis 1999;9: Thomas F et al. Hypertension 2001;37: Palatini P et al. Arch Intern Med 2002;162: These have generally shown that higher baseline heart rate was associated with increased cardiovascular and overall mortality after adjusting for blood pressure and other relevant factors

7 Age-adjusted 2-year rate per 1000 Age-adjusted 2-year rate per 1000 Influence of heart rate on mortality among persons with hypertension: the Framingham Study CHD CVD All cause Men CHD CVD All cause Women < Heart rate (beats/min) 0 < Heart rate (beats/min) Association of heart rate with mortality rate among men and women with hypertension from 36 year follow-up of the Framingham Study Adapted from: Gillman MW et al. Am Heart J 1993;125:

8 Influence of heart rate on mortality in a French population with normotensive and hypertensive subjects Deaths/year/1000 subjects P = 0.01 CHD Mortality Heart rate (bpm) <60 60 HR 80 80< HR 100 > Normotensive Men Hypertensive Normotensive Hypertensive Women In men, but not women, HR was associated with all-cause and cardiovascular mortality and: 1) There was a strong association with CHD but not cerebrovascular mortality 2) This was independent of age and hypertension 3) In subjects with high pulse pressure (>65 mmhg), high HR was not associated with increased CV mortality Adapted from: Benetos A et al. Hypertension 1999;33:44-52

9 Association of heart rate with cardiovascular events in hypertensive subjects: in-treatment heart rate Recent studies have examined the relationship between intreatment heart rate and outcome in subjects with hypertension The Glasgow Blood Pressure Clinic The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial The Losartan Intervention For Endpoint reduction (LIFE) study The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) Some, but not all of these, have shown that in-treatment heart rate may be a better predictor than baseline heart rate of cardiovascular events or the development of heart failure

10 Hazard Ratio Four-corner analysis Hazard Ratio Change in heart rate Resting heart rate pattern during follow-up and mortality in hypertensive patients Adjusted cumulative risk of all-cause death P = Low-low High-low Low-high High-high to -1 0 to 4 5 Baseline and final heart rate < or > 80 beats/min Baseline and final heart rate Categorical change In patients attending the Glasgow Blood Pressure Clinic, all-cause and cardiovascular mortality increased with baseline and final heart rate. The highest risk was seen in patients whose heart rate increased during follow up by 5 beats/min Adapted from: Paul L et al. Hypertension 2010;55:

11 Cumulative primary event rate In-trial heart rate predicted cardiovascular events even with good blood pressure control VALUE trial 14% 12% 10% 35% 50% 8% 6% 4% 2% 0% 5 th HR quintile and Uncontrolled BP Other 4 quintiles and Uncontrolled BP 5 th HR quintile and Controlled BP Other 4 quintiles and Controlled BP Adapted from: Julius S et al. Am J Cardiol. 2012; 109(5):

12 % with event All-cause and cardiovascular mortality in relation to changing heart rate during treatment of hypertension LIFE study 15 Heart rate 84 Heart rate < 84 All-cause mortality Month The Losartan Intervention For Endpoint reduction (LIFE) study Persistence or development of HR 84 was associated with a 55% greater risk of cardiovascular (CV) death (95% CI: %) and a 79% greater adjusted risk of all-cause mortality (95% CI: %) (after adjusting for treatment with losartan vs. atenolol, baseline risk factors for death, baseline heart rate (HR), baseline and in-treatment systolic (SBP) and diastolic (DBP) blood pressure, incident myocardial infarction, and the known predictive value of baseline and in-treatment QRS duration and ECG LVH) Adapted from: Okin PM et al. Eur Heart J 2010; 31:

13 New-onset HF Rate /1,000 patient-years Effect of changing heart rate during treatment of hypertension on incidence of heart failure LIFE study HR 84 HR < 84 Adjusted Hazard Ratio 2.59 (95% CI ) In-treatment heart rate was a better predictor of new heart failure than baseline heart rate. Persistence or development of a heart rate 84 beats/min was associated with 159% greater risk of heart failure Adapted from: Okin PM et al. Am J Cardiol. 2012; 109(5):

14 Event rate per 100 person years (95% CI) Baseline heart rate, antihypertensive treatment, and prevention of cardiovascular outcomes in ASCOT Total cardiovascular events and procedures Amlodipine-based vs.atenolol-based therapy unadjusted hazard ratio: 0.81 (p < 0.001). Overall < < < < Baseline heart rate categories (beats/min) Atenolol Amlodipine Total cardiovascular events and procedures were reduced in patients allocated amlodipine-based therapy compared with atenolol-based therapy and this effect was not attenuated at higher baseline heart rates. Similar results were seen for coronary and total stroke outcomes Adapted from: Poulter NR et al. J Am Coll Cardiol. 2009;54:

15 Relative Risk of Myocardial Infarction Resting heart rate pattern during follow-up and mortality in hypertensive patients VACS (1982) 1.3 r = , p = y = *x ASCOT HAPPHY Yurenev LIFE ELSA INVEST IPPPSH Heart rate at Trial End Beta Blocker Group (beats/min) ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial: Atenolol vs. amlodipine ELSA = European Lacidipine Study on Atherosclerosis: Atenolol vs. lacidipine HAPPHY = Heart Attack Primary Prevention in Hypertension trial: Atenolol/metoprolol vs. BFZ/HCTZ INVEST = International Verapamil SR and Trandolapril study: Atenolol vs.verapamil SR IPPPSH = International Prospective Primary Prevention Study in Hypertension: Oxprenolol vs. placebo LIFE = Losartan Intervention for End point Reduction trial: Atenolol vs. losartan VACS = Veterans Administration Cooperative Study Group on Antihypertensive Agents: Propranolol vs. HCTZ Yurenev, 1992: Propranolol vs. diuretic Adapted from: Bangalore S et al. J Am Coll Cardiol 2008;52:

16 Heart rate reduction with beta-blockers in hypertension: Helpful or harmful? The reduction of heart rate in acute myocardial infarction and postmyocardial infarction with beta-blockers has been shown to reduce infarct size and mortality, and similar beneficial effects of heart rate reduction with beta-blockers have been observed in meta-analyses of trials of patients with heart failure and angina pectoris However, the analysis from ASCOT-BPLA and the meta-analysis of studies of beta-blockers in hypertension (Bangalore, 2008), which included ASCOT-BPLA, suggest that in hypertension, reduction of heart rate with beta-blockers, or at least with atenolol, is not beneficial This lack of benefit has been attributed in part to adverse effects of heart rate reduction on the central aortic pressure as shown by the CAFE (Conduit Artery Function Evaluation) sub-study of ASCOT-BPLA Williams B et al. J Am Coll Cardiol. 2009; 54(8):

17 mmhg mmhg Heart rate reduction increases central systolic blood pressure augmentation 110 Normal heart rate Peak SBP augmentation Peak SBP augmentation at lower heart rate 100 Aortic pressure wave Forward ejected pressure wave Backward reflected pressure wave End of ejection duration The reflected pressure wave returns earlier at slower heart rates and augments the peak central SBP 70 Onset of the forward-ejected wave End of ejection duration at low heart rate Time to return at the aorta of the backward-reflected wave Adapted from: Safar ME et al. Circulation 2009;119:9-12.

18 Increased heart rate is directly harmful for the heart Diastolic duration Heart Rate Perfusion of coronary arteries Cardiac work Oxygen supply Oxygen needs Oxygen supply/needs ratio Adapted from: Palatini P. Eur Heart J Supplements 1999 (Suppl B):B3-B9.

19 Vascular benefits of heart rate reduction Risk factor Endothelial dysfunction Atherosclerosis Plaque rupture Reduction of vascular oxidative stress (mouse) 1 Restoration of endothelial function (mouse) 1,2 Restoration of erectile function (mouse) 3 Reduction of vascular wall stress (rat) 4 Inhibition of atherogenesis (monkey, mouse) 1,3,5,6 Stimulation of angiogenesis (rat, pig) 7,8 Reduction of myocardial ischemia (pig, human) 9,10,11 Vascular event Reduction of hospital admissions for angina, MI and coronary revascularization 12,13 Adapted from: Custodis F et al. J Am Coll Cardiol 2010;56: Custodis F et al. Circulation 2008;117: Drouin A et al. Br J Pharmacol 2008;154: Baumhäkel M et al. Atherosclerosis 2010;212: Albaladejo P et al. J Vasc Res 2003;40: Beere PA et al. Science 1984;226: Beere PA et al. Arterioscler Thromb 1992;12: Zheng W et al. Circ Res 1999;85: Li J et al. J Clin Invest 1997;100: Heusch G et al. Eur Heart J 2008;29: Tardif JC et al. Eur Heart J 2005;26: Borer JS et al. Circulation 2003;107: Fox K et al. Eur Heart J 2009;30: Fox K et al. Lancet 2008;372:

20 Annual Change in Atheroma volume (mm 3 ) Beta-blockers can slow progression of coronary atherosclerosis Without -blocker With -blocker LDL-cholesterol <median -2 LDL-cholesterol median (2.2 mmol/l or 86 mg/dl) -4 Without -blocker -6 With -blocker Post hoc, pooled analysis of individual patient data from 4 IVUS trials showed annual change in atheroma volume was statistically significantly less in patients who received beta-blockers Adapted from: Sipahi I et al, Ann Intern Med. 2007;147:10-18.

21 Adverse outcome incidence (%) Estimated hazard ratio On-treatment resting heart rate predicted adverse outcomes in CAD patients with hypertension - INVEST Adverse outcome Hazard ratio Mean follow-up heart rate (beats/min) Nadir for follow-up resting heart rate was 59 beats/min Adapted from: Kolloch R et al, Eur Heart J 2008;29:

22 Cumulative survival (%) Beta-adrenergic receptor gene polymorphisms and treatment outcomes in hypertension: INVEST-GENES SBP/DBP A: Non-S49-R389 + VE 134/78 B: Non-S49-R389 + AT 134/ C: S49-R389 + AT 134/78 96 D: S49-R389 + VE 134/ Time to event (months) 1-adrenergic receptor haplotype: S49-R389 is the more common and more responsive form Adapted from: Pacanowski MA et al. Clin Pharmacol Ther. 2008;84(6):

23 How should heart rate be reduced in hypertension? Beta-blockers Beta-blockers are effective in reducing cardiovascular events and mortality in acute coronary syndromes and stable angina and some beta-blockers are effective in reducing mortality in heart failure. These benefits appear to be related to heart rate reduction, and but the reduction of heart rate with beta-blockers (mainly atenolol) in hypertension has not been proven to be beneficial. Non-dihydropyridine calcium channel blockers Verapamil and diltiazem reduce heart rate and blood pressure and have shown benefits in coronary artery disease (CAD), but are not indicated in heart failure and the benefit of heart rate reduction with these drugs in hypertension has not been extensively assessed. Ivabradine Ivabradine is a specific inhibitor of the I(f) current in the sinoatrial node and reduces heart rate without affecting blood pressure, myocardial contractility, intracardiac conduction, or ventricular repolarisation. It has shown benefits through heart rate reduction in patients with heart rates 70 b.p.m. In the BEAUTIFUL (morbidity-mortality EvAlUaTion of the I(f) inhibitor ivabradine in patients with coronary disease and left-ventricular dysfunction) Trial, (Fox K et al. Lancet 2008; 372: ) and in SHIFT(Systolic Heart failure treatment with the I(f)-inhibitor ivabradine Trial), (Swedberg K et al. Lancet 2010; 376: ; Böhm M et al. Lancet 2010; 376: ) but there is no study to show it is beneficial in hypertension.

24 Beta-blockers can intervene at many points in the cardiovascular continuum Βeta-blockade (part of the benefits through heart rate reduction)? Increased heart rate Adapted from: Willenheimer R & Erdmann E. Eur Heart J Suppl 2009;11:A1-A2.

25 Conclusions In patients with hypertension, a high baseline heart rate or an increase in heart rate during treatment is associated with increased risk of cardiovascular events and development of heart failure The current evidence, which is predominantly with atenolol, does not support the use of beta-blockers to reduce this increased cardiovascular risk associated with increased heart rate However, careful assessment and intensified therapy of risk factors for cardiovascular events and development of heart failure may be warranted in such patients Further studies are required to determine if newer vasodilating beta-blockers or those beta-blockers with evidence of benefit in heart failure may have advantages in relation to the cardiovascular risks related to increased heart rate in hypertension