Heart rate as a treatable risk factor in cardiovascular disease






Martin R. COWIE, MD
FRCP, FRCP (Edin), FESC
National Heart and Lung Institute
Imperial College London and Royal Brompton Hospital
London, UNITED KINGDOM

Heart rate as a treatable risk factor in cardiovascular disease


by M. R. Cowie, United Kingdom



There is increasing evidence that elevated resting heart rate is associated with increased cardiovascular morbidity and mortality, both in the general population and in patients with cardiovascular disease. Furthermore, data now suggest that heart rate is a treatable risk factor in patients with cardiovascular disease, and not simply a prognostic marker. Heart rate meets the key criteria for risk factor status. Until recently, despite considerable epidemiological evidence on the association between heart rate and cardiovascular outcomes, and the apparent benefit of reducing raised heart rate, there has been uncertainty whether the relationship between heart rate and cardiovascular disease is causal. This is because conventional drugs that reduce heart rate—such as β-blockers—have multiple effects on the cardiovascular system and so it has been difficult to separate their effect on heart rate from their other properties. Recent studies with ivabradine, a drug that lowers heart rate but has no other direct cardiovascular effects, have allowed the effect of heart rate lowering per se to be evaluated. The new data provide persuasive evidence that lowering raised heart rate is clinically beneficial in heart failure and coronary artery disease. In hypertension, heart rate is of prognostic importance, but has not yet been proven to be a modifiable risk factor.

Medicographia. 2012;34:387-394 (see French abstract on page 394)



There is increasing epidemiological and clinical trial evidence that raised resting heart rate is independently associated with increased cardiovascular morbidity and mortality, both in the general population and in patients with cardiovascular disease.

In the literature, heart rate has to date tended to be described as a risk or prognostic marker, rather than as a risk factor, indicating that the observed association between heart rate and cardiovascular outcomes is not necessarily causal.

A risk factor needs to fulfill certain criteria of causation, as first put forward by epidemiologist and statistician Sir Austin Bradford Hill in 1965 (Figure 1, page 388).1 This article reviews current evidence on the importance of heart rate in cardiovascular disease (coronary artery disease, acute coronary syndromes, heart failure, and hypertension) and considers to what extent heart rate fulfills relevant Bradford-Hill criteria. With the increasing body of evidence, can heart rate now be described as a true modifiable risk factor and a target for treatment?


Figure 1
Figure 1. The Bradford Hill criteria (left).
Sir Austin Bradford Hill, CBE, FRS, PhD, DSC (1897-1991).

After reference 1: Hill. Proc Roy Soc Med. 1965;58:295-300.
Photograph reproduced from Sir Austin Bradford Hill Archive. ©, London
School of Hygiene and Tropical Medicine. http://www.cardiff.ac.uk/insrv/libraries/
scolar/archives/bradfordhill/index.html


Plausibility

One of the risk factor criteria is plausibility, ie, is there a pathophysiological rationale for the suggestion that raised heart rate is associated with increased cardiovascular disease?

In animal studies, accelerated heart rate is associated with cellular signaling events leading to vascular oxidative stress, endothelial dysfunction, and acceleration of atherogenesis.2 The precise mechanisms that link heart rate and cardiovascular outcomes have not been defined.2-4 However, elevated heart rate is thought to play a central role in the pathophysiology of coronary artery disease, leading to acute ischemia in patients with stable angina,5 and also directly affecting the progression of coronary atherosclerosis4,6 and plaque rupture.7





Increased risk in patients with coronary artery disease may reflect autonomic imbalance, but experimental and clinical observations indicate that elevated heart rate per se may also have direct detrimental effects on cardiovascular function by increasing the ischemic burden or via local hemodynamic forces on the endothelium and arterial wall, which can promote progression of atherosclerosis and plaque rupture (Figure 2).2,3

Elevated heart rate was shown to be a predictor of the progression of coronary atherosclerosis in young men after myocardial infarction, and this appeared to be independent of other well-established risk factors.6 Another study, which retrospectively analyzed angiographic data in 106 patients with coronary artery disease, showed a positive association between mean heart rate >80 beats per minute (bpm) and plaque disruption.7 In a recent population-based study of people without clinical cardiovascular disease at baseline, elevated resting heart rate was associated with increased incidence and progression of atherosclerosis, as demonstrated by increased coronary artery calcium.4 There is therefore considerable evidence for the biological plausibility of heart rate as a risk factor in coronary artery disease.

There is also a pathophysiological rationale for adverse outcomes from elevated heart rate in patients with heart failure, since increased heart rate is associated with increased oxygen demand, reduced ventricular efficiency, and reduced ventricular relaxation.8 Heart rate reduction decreases energy expenditure, increases blood supply by prolonging diastole, improves force-frequency associations, and reduces ventricular loading.9

Strength and consistency of association and graded response

Other important considerations in determining causality are the strength and consistency of the association and whether there is a biological gradient (or “dose response”). Heart rate fares well on these criteria. Many studies have shown that elevated resting heart rate is associated with worse cardiovascular outcomes, both in the general population and in patients with cardiovascular disease.

_ General population
In the Framingham study, the 30-year follow-up showed increased heart rate to be associated with an increase in allcause mortality and cardiovascular mortality at all ages in both men and women.10

The Paris Prospective Study involved 5139 men aged 42 to 53 years, initially free of cardiovascular disease, in whom resting heart rate was measured every year for 5 years, with follow- up for a mean of 23 years. Heart rate at rest and heart rate change over 5 years were both predictors of mortality, independent from standard cardiovascular risk factors. After adjustment for confounding factors, and compared with sub- jects with unchanged heart rates (from –4 to +3 bpm) during the 5 years, subjects with decreased heart rates (>4 bpm) had a 14% decreased mortality risk (P=0.05), whereas subjects with increased heart rates (>3 bpm) had a 19% increased mortality risk (P<0.012).11 The study also showed that the heart rate profile during exercise and recovery was a predictor of sudden death from myocardial infarction, and that sudden death increased in people with a resting heart rate >75 bpm (relative risk [RR], 3.92; confidence interval [CI], 1.91-8.00).12


Figure 2
Figure 2. Suggested mechanisms whereby an elevated heart rate leads to adverse
outcomes in patients with coronary artery disease.

Abbreviations: CV, cardiovascular; HRV, heart rate variability.
After reference 3: Lang et al. Atherosclerosis. 2010;212:1-8. © 2010, Elsevier Ireland Ltd.



The FINRISK study (FINland cardiovascular RISK study) confirmed a strong, graded, independent relationship between resting heart rate and incident cardiovascular disease in both men and women.13 This study involved over 20 000 people with no preexisting cardiovascular disease, with a median follow- up of 12 years. Hazard ratios for cardiovascular disease mortality for each 15-bpm increase in resting heart rate were 1.24 in men and 1.32 in women, after adjustment for standard risk factors. A resting heart rate of >90 bpm compared with one of <60 bpm was associated with an almost 2-fold greater risk of cardiovascular mortality in men and a 3-fold increased risk in women (Figure 3).

_ Coronary artery disease
The prognostic value of resting heart rate was shown in an analysis of the CASS registry (Coronary Artery Surgery Study).14 A total of 24 913 subjects with suspected or proven stable coronary artery disease were followed for a median of 14.7 years. High resting heart rate was a predictor for total and cardiovascular mortality, independent of other risk factors. The association was found in all subgroups analyzed. Patients with resting heart rates ≥83 bpm at baseline had a significantly higher risk of cardiovascular mortality (hazard ratio [HR], 1.31; CI, 1.15-1.48; P<0.0001) compared with those with baseline resting heart rates ≤62 bpm. More recently, investigators from the TNT trial (Treating to New Targets) reported increased resting heart rate to be a strong independent risk factor in a cohort of well-treated patients with stable coronary artery disease, followed for a median of 4.9 years. There was a linear relationship between resting heart rate and cardiovascular outcomes: the rate of major cardiovascular events was 11.9% in those with a baseline heart rate of ≥70 bpm versus 8.8% in those with a baseline heart rate of <70 bpm (Figure 4, page 390).15


Figure 3
Figure 3. Cardiovascular disease mortality according to resting heart rate in healthy men and women in the FINRISK study (FINland cardiovascular RISK study).

After reference 13: Cooney et al. Am Heart J. 2010; 159:612-619. © 2010, Mosby, Inc.



Figure 4
Figure 4. Kaplan-Meier estimates of the cumulative incidence of a first major cardiovascular event during follow-up by baseline heart rate (≥70 vs <70 bpm) in patients with stable coronary artery disease in the TNT trial (Treating to New Targets). HR=hazard ratio; P value determined using log-rank test.

After reference 15: Ho et al. Am J Cardiol. 2010;105:905-
911. © 2010, Elsevier Inc.



Analysis of data from the placebo group of the BEAUTIFUL randomized controlled trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) demonstrated a gradient between heart rate and cardiovascular outcome and confirmed the prognostic importance of heart rate in patients with stable coronary artery disease and left ventricular dysfunction receiving appropriate background therapy.16 A subgroup analysis compared outcomes in patients with a baseline heart rate of ≥70 bpm with those with a heart rate of <70 bpm. Patients with the higher heart rates had increased risk of cardiovascular death (34%; P=0.0041), admission to hospital for heart failure (53%; P<0.0001), admission to hospital for myocardial infarction (46%; P=0.0066), and coronary revascularization (38%; P=0.037), after adjustment for other predictors of outcomes. For every increase of 5 bpm, there were increases in cardiovascular death (8%; P=0.0005), admission to hospital for heart failure (16%; P<0.0001), admission to hospital for myocardial infarction (7%; P=0.052), and coronary revascularization (8%; P=0.034).

The prognostic effect of heart rate has also been shown in acute coronary syndromes. A US study of 1807 patients with acute myocardial infarction found that both in-hospital and 1-year mortality increased with increasing admission heart rate. Mortality from hospital discharge to 1 year was also related to heart rate at discharge.17 In this study, heart rate was a more powerful predictor of later mortality than assessment of left ventricular function after arrival in hospital, suggesting that elevated heart rate does not only reflect depressed cardiac function. Similarly, the GISSI studies of acute myocardial infarction (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico) showed a progressive increase in in-hospital mortality with increasing heart rate, and multivariate analysis showed that heart rate was an independent prognostic factor. Increasing heart rate at discharge was also associated with increased 6-month mortality.18

_ Hypertension
There is considerable evidence that raised heart rate is associated with increased risk in patients with hypertension. For example, the Framingham study identified resting heart rate as a potential independent risk factor in hypertensive patients. Among 4530 men and women with raised blood pressure who were not taking antihypertensive medication, each heart rate increase of 40 bpm was associated with odds ratios for all-cause mortality of 2.18 for men and 2.14 for women and odds ratios for cardiovascular mortality of 1.68 for men and 1.70 for women.19

In the HARVEST study of individuals with stage 1 (untreated) hypertension (Hypertension and Ambulatory Recording VEnetia Study), a persistently high heart rate was an independent predictor of future sustained hypertension.20 Heart rate measurement at baseline and during the first few months of follow- up gave prognostic information over and above that provided by baseline office and ambulatory blood pressure. In the placebo arm of the Syst-Eur trial (Systolic Hypertension in Europe), which involved patients aged 60 years or older, a clinic heart rate >79 bpm was a significant predictor of allcause, cardiovascular, and non-cardiovascular mortality.21

The association between resting heart rate and adverse outcomes in elderly hypertensive patients with coronary artery disease was assessed in the INVEST population (INternational VErapamil-SR/trandolapril Study),22 which showed that both higher baseline and, particularly, follow-up resting heart rates were associated with adverse outcome, with increased risk starting at a resting heart rate of 75 bpm.

In 2010, the Glasgow Blood Pressure Clinic study investigated the relationship between resting heart rate and outcomes in a cohort of 4065 patients with mild-to-severe hypertension. Heart rate was measured at baseline and at final follow-up (mean follow-up, 897 days; range, 7 to 7087 days). Heart rate was an independent predictor of all-cause, cardiovascular, and ischemic heart disease mortality. In this study, change in heart rate during follow-up was a better predictor of risk than baseline or final heart rate, the highest risk being in patients whose heart rate increased by ≥5 bpm.23 After correction for rate-limiting therapy (β-blockers and calcium channel blockers), heart rate remained a significant independent risk factor, suggesting that the relationship between heart rate and mortality cannot just be explained by the use of heart rate–lowering interventions.

A further study measured resting heart rate annually during treatment in 9190 patients with hypertension and left ventricular hypertrophy. After a mean follow-up of 4.8 years, higher in-treatment heart rates were shown to be strongly associated with increased risk of cardiovascular and all-cause mortality, independent of blood pressure lowering or other risk factors.24

_ Heart failure
Raised heart rate has also been shown to be associated with increased risk of mortality and morbidity in patients with heart failure. Analysis of data from the CHARM trials (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) in patients with chronic heart failure showed an 8% increase in the risk of cardiovascular death or heart failure hospitalization for every 10-bpm increase in heart rate.25 The placebo groups of two major trials assessing the effect of β-blockers in heart failure have also provided data on the prognostic importance of heart rate, with evidence of increased mortality with increasing baseline heart rate.26, 27

More recent data come from the placebo arm of the SHIFT study (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) in patients with chronic heart failure, which showed a continuous direct association between baseline heart rate and outcomes.9 Patients with the highest heart rates (≥87 bpm) had a more than 2-fold higher risk for the primary composite end point (cardiovascular death or first hospital admission for worsening heart failure) than patients with the lowest heart rates (70 to <72 bpm; HR, 2.34; 95% CI, 1.84-2.98; P<0.0001). The risk of these end-point events increased by 3% with every bpm increase from baseline heart rate and by 16% for every 5-bpm increase (Figure 5).

Temporal relationship

A temporal relationship is another risk factor criterion. This issue was specifically addressed in the FINRISK study of men and women without preexisting cardiovascular disease.13 To investigate whether raised heart rate was an independent risk factor or merely a marker of subclinical disease, data were reanalyzed excluding all fatal events that occurred in the first 2 years of follow-up. There was no change in hazard ratios, demonstrating a temporal sequence consistent with causality.


Figure 5
Figure 5. Kaplan-Meier cumulative event curves for the primary composite end point
(cardiovascular death or first hospital admission for worsening heart failure) in the
placebo group (n=3264) of the SHIFT study (Systolic Heart failure treatment with the
If inhibitor ivabradine Trial), according to groups defined by quintiles of heart rate at
baseline. The log-rank P value is shown for the difference between the Kaplan-Meier
curves.

After reference 9: Böhm et al. Lancet. 2010;376:886-894. © 2010, Elsevier Ltd.


Experimental evidence

Experimental evidence is a key criterion for risk factor status, providing the strongest support for causation: do disease rates fall when the proposed causal agent has been eliminated?

Experimental data in animals show that lowering heart rate reduces atherosclerosis.28,29 There is also considerable evidence of the impact of heart rate reduction in patients with cardiovascular disease: the beneficial effects of β-blockers in acute myocardial infarction and heart failure have been shown to be related, at least in part, to heart rate reduction. However, the specific effect of heart rate lowering has been uncertain as the drugs that lower heart rate (primarily β-blockers) have multiple pharmacological effects and it has not been possible to separate their effect on heart rate from other potential protective mechanisms—such as antiarrhythmic effects— and hence to determine whether the benefit is related to the drug class or to heart rate reduction per se.

The development of the pure heart rate–lowering drug ivabradine provided an opportunity to further evaluate the effect of heart rate lowering in randomized controlled trials. Ivabradine acts only on sinoatrial node If channels. It lowers heart rate and has no other known cardiovascular effects.

_ Coronary artery disease
Ivabradine was evaluated in the BEAUTIFUL trial in patients with stable coronary artery disease and left ventricular dysfunction. Ivabradine treatment did not significantly affect the primary composite end point (cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new-onset or worsening heart failure) in the overall trial population. However, in a subgroup of patients with baseline heart rates above 70 bpm, ivabradine treatment reduced the risk of fatal and nonfatal myocardial infarction (a secondary end point) by 36% (P=0.001). This benefit was observed despite the fact that 87% of patients were receiving background β-blocker treatment.30 The study therefore strongly suggests clinical benefit from lowering raised heart rate.

There are as yet no data proving that heart rate reduction in acute coronary syndromes improves survival, but analysis of postmyocardial infarction β-blocker trials indicates that a reduction in resting heart rate is an important determinant of clinical benefit.31,32 A meta-regression of these trials investigated the relationship between reduction in resting heart rate and magnitude of clinical benefits. The results suggest that the beneficial effect of β-blockers and calcium channel blockers on mortality and nonfatal reinfarction in postmyocardial infarction patients is proportional to the extent of reduction in resting heart rate, with the benefit related to heart rate lowering rather than specific drug class.31 Each 10-bpm reduction in resting heart rate was estimated to reduce the relative risk of cardiac death by about 30%.

_ Heart failure
Analysis of the major heart failure trials showed that treatments that reduced heart rate were associated with reduced mortality while those that increased heart rate tended to increase mortality (Figure 6).33

As with the postmyocardial infarction trials, data suggest that heart rate reduction contributes, certainly in part, to the clinical benefits of β-blockers in heart failure. For example, multivariate analysis of the CIBIS II trial of bisoprolol in chronic heart failure (Cardiac Insufficiency BIsoprolol Study II)26 showed that the best outcome (in terms of survival and reduction in hospital admissions) was in patients with the lowest baseline heart rate and the greatest heart rate change. The study also showed that the beneficial effect of bisoprolol on survival was similar at any level of baseline heart rate and heart rate change, indicating that heart rate reduction is not the only mechanism for β-blocker benefit in heart failure. In the COMET trial (Carvedilol Or Metoprolol European Trial),34 heart rate achieved with β-blocker therapy had prognostic value for mortality in heart failure patients.

A recent meta-regression analysis of β-blocker trials in heart failure showed a statistically significant association between the magnitude of heart rate reduction and survival benefit.35

For every heart rate reduction of 5 bpm the relative risk of death decreased by 18% (CI, 6%-29%). Another analysis of these trials36 found a close relationship between all-cause annualized mortality rate and heart rate and a strong correlation between change in heart rate and change in ejection fraction.


Figure 6
Figure 6. Relationship between change in heart rate and mortality
in chronic heart failure trials.

After reference 33: Kjekshus and Gullestad. Eur Heart J. 1999;1(suppl H):H64-
H69. © 1999, The European Society of Cardiology.



More definitive evidence of the benefit of heart rate lowering came from the SHIFT randomized placebo-controlled trial, which assessed the pure heart rate–lowering drug ivabradine in 6558 patients with symptomatic heart failure and an ejection fraction of ≤35%, sinus rhythm, and resting heart rates of ≥70 bpm.37 Patients were on stable background therapy, including a β-blocker if tolerated. Over a median follow-up of 22.9 months, there was an 18% relative risk reduction for the primary composite end point of cardiovascular death or hospital admission for worsening heart failure (P<0.0001). The effect was mainly driven by hospital admissions for worsening heart failure, which were reduced by 26% (P<0.0001), and deaths due to heart failure (relative risk reduction, 26%; P=0.014). Treatment benefit was shown to be related to heart rate reduction, with a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes.9 SHIFT thus demonstrated for the first time the beneficial effects of heart rate reduction alone in patients with systolic heart failure.

_ Hypertension
Resting heart rate has been shown to be a prognostic marker in patients with hypertension, but there is as yet no specific evidence that reducing heart rate is linked to improved outcome in patients with hypertension.

Conclusion: strength of evidence for heart rate as a cardiovascular risk factor

The Bradford Hill criteria1 are intended as guidelines to help determine whether an observed association reflects cause and effect. The more criteria that are met, the more likely it is that the association is causal. There is increasing evidence for heart rate as a true risk factor rather than simply a marker of risk in cardiovascular disease: it meets the criteria of plausibility (although the exact mechanisms remain to be determined), strength of association, dose response, consistency, and temporality. There is also now increasing evidence of improved outcomes following the reduction of raised heart rate, thus meeting the important “experimental evidence” criterion. The recent studies with ivabradine provide persuasive evidence that heart rate is a true modifiable risk factor in heart failure and in coronary artery disease. _

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Keywords: causality; heart rate; ivabradine; risk factor