Is heart rate optimally controlled in patients with coronary artery disease in clinical practice?



by C. Daly, Ireland

Caroline DALY MB, PhD, MRCPI
CREST Unit St James’s Hospital
Dublin, IRELAND

Myocardial oxygen demand is primarily controlled by heart rate, which also controls myocardial oxygen supply, and an elevated heart rate can trigger myocardial ischemia. Furthermore, emerging evidence suggests that as an independent cardiovascular risk factor, heart rate may be comparable in importance to smoking, dyslipidemia, or hypertension, yet this is often overlooked. Data on the control of heart rate in clinical practice is scarce, and that which do exist, ie, in registries of acute coronary syndromes and post–myocardial infarction populations, suggest that elevated resting heart rate is common. A resting heart rate of >75 beats per minute, the level above which the risk of cardiac events begins to increase, is found in a substantial proportion of patients post–myocardial infarction—up to one third of women and one quarter of men. Observational data from studies of preoperative β-blockade, and meta-analysis of the effect of preoperative β-blockade on mortality reduction, point to considerable inter-patient variability in heart rate response to β-blockade. There are also indications that a substantial proportion of patients fail to achieve target heart rates (over 25%) and that attainment of target heart rate is necessary to achieve cardioprotection with β-blockade. Data from the Euro Heart Survey of Angina suggest that heart rate control is not optimal in the stable angina setting, despite its proven benefits with regard to reducing ischemia, with multiple factors including comorbidity affecting the use of β-blockers.

Medicographia. 2009;31:364-370 (see French abstract on page 370)

Heart rate and ischemia

Heart rate is the primary determinant of myocardial oxygen demand, and it also controls myocardial oxygen supply.1 Experimental studies indicate that increased heart rate is associated with increased myocardial oxygen demand through the combined effects of increased cardiac work and myocardial oxygen consumption, and reduced diastolic perfusion time and subendocardial perfusion.2-4

Numerous experimental studies have shown that elevated heart rate triggers most episodes of myocardial ischemia.5-7 Data published in the early 1990s gathered by the Angina and Silent Ischemia Study (ASIS) Group from a sample of 50 coronary artery disease (CAD) patients treated with a â-blocker, calcium channel blocker, or placebo, suggest that most episodes of ambulatory ischemia (>80%) are associated with preceding increases in heart rate, and that the likelihood of ischemia development is directly related to baseline resting heart rate. Myocardial ischemia was more than twice as likely in patients with a baseline heart rate of ≥80 beats per minute (bpm) rather than <60 bpm, and the anti-ischemic activity of each type of medication was related chiefly to each drug’s ability to reduce heart rate.5

A considerable amount of the available data regarding the effect of elevated heart rate on ischemia was published over 15 years ago, and although guidelines for the management of angina emphasize the need to achieve target heart rates to control ischemia,8,9 the significance of raised resting heart rate as a major prognostic indicator and target for treatment has only become more widely realized in the clinical community in recent times.1,10 Despite its simplicity, heart rate may be comparable in importance as an independent cardiovascular risk factor to smoking, dyslipidemia, or hypertension, yet this is often overlooked.

Heart rate and prognosis

There have been several large observational studies showing elevated heart rate to be associated with adverse outcome in both the coronary disease population and the general population.11,12 A key study in this regard showed resting heart rate to be a predictor of total and cardiovascular mortality in nearly 25 000 patients with CAD.13 Patients from the Coronary Artery Surgery Study registry were followed up for a median 14.7 years, and those with a resting heart rate of ≥83 bpm had significantly increased risks of total mortality (hazard ratio [HR] 1.32; P<0.0001) and cardiovascular mortality (HR 1.31; P<0.0001), after adjustment for other clinical variables.13 In BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), a large study of CAD patients with left ventricular systolic dysfunction, patients with a heart rate of ≥70 bpm had a 34% increased risk of cardiovascular death (P=0.0041), a 53% higher risk of admission to hospital for heart failure (P<0.0001), a 46% greater risk of admission to hospital for myocardial infarction (P=0.0066), and a 38% higher risk of coronary revascularization (38%; P=0.037).14 The INternational VErapamil SR/Trandolapril study (INVEST), which included over 22 000 patients with stable CAD and hypertension randomized to verapamil or atenolol, demonstrated a similar linear increase in the risk of cardiovascular events with increasing resting heart rate, with risk increasing significantly at a heart rate of approximately 75 bpm.15 And the effects of heart rate on outcome are evident across the spectrum of coronary presentations. A recent report on prognostic indicators in a low risk population presenting with acute coronary syndromes (ACS; n=15 000) selected heart rate at presentation as an important clinical indicator of the likelihood of freedom from events, with lower heart rates associated with fewer events during follow-up.16

Treatment of heart rate

Heart rate reduction has been associated with clinically important benefits in various subtypes of coronary heart disease.1 Pooled data from 8 randomized, double-blind studies of β-blockade revealed that during the evolution of myocardial infarction (ie, within 12 hours of symptom onset), a decrease in heart rate of ≥14 bpm was linked to a 25% to 30% decrease in infarct size.17 Moreover, in large-scale, pooled analyses of post-infarct patients, a mean heart rate decrease of approximately 10 bpm was associated with reduced risks of approximately 20% to 25% in total mortality, cardiac death, and nonfatal reinfarction.17,18 In specific studies of angina and silent myocardial ischemia prevention, the most marked efficacy has been documented for agents with the most sustained decreases in heart rate. For instance, during 24-hour ambulatory echocardiographic monitoring in ASIS in patients with stable CAD, β-blockade significantly reduced the mean number of asymptomatic ischemic episodes by 57% (P<0.0001), and the mean duration of ischemia by 87% (P<0.0001).19 The American College of Cardiology and American Heart Association now recommend a target resting heart rate of 60 bpm for β-blocker–treated patients
with stable angina.8

Heart rate lowering in practice

Despite the proven benefits of heart rate reduction in reducing ischemia and angina, and the association of lower heart rates with improved prognosis, only relatively limited data exist on the attainment of heart rate targets in clinical practice or the use of pharmacological therapies to achieve target heart rate. The vast majority of studies on pharmacological therapies or revascularization in CAD populations do not even report resting heart rate at baseline, even when blood pressure is reported. The analogy may be drawn between this and earlier scant reporting of either cholesterol levels or the use of antilipid or antiplatelet therapies. Resting heart rate and heart rate during follow-up are reported in a handful of studies that have looked at management of ischemia in stable angina, such as Total Ischaemic Burden European Trial (TIBET), a study using atenolol,20 and Angina Prognosis Study In Stockholm (APSIS), a study using metoprolol,21 as well as more recent trials such as the aforementioned INVEST and BEAUTIFUL. But accurate data regarding the actual heart rates routinely encountered in “real world” patients are rare.

_ Acute coronary syndromes and myocardial infarction
The Global Registry of Acute Coronary Events (GRACE) was designed to reflect an unbiased population of patients with ACS, irrespective of geographical region. More than 120 hospitals located in 14 countries in North and South America, Europe, Australia, and New Zealand contributed patients who had been admitted with a presumptive diagnosis of ACS (that is, had symptoms consistent with acute ischemia), and had at least one of the following: electrocardiogram (ECG) changes consistent with ACS, serial increases in serum biochemical markers of cardiac necrosis, and documentation of CAD. In this population (n=15 757), the median heart rate (interquartile range) was 76 bpm (65-90 bpm). In those free of events, the median heart rate was 75 bpm (64-88 bpm), and in those who went on to die or develop further myocardial infarction or revascularization, it was 83 bpm (70-100 bpm).16

Table
Table. Heart rate and associated risk of mortality in the GISSIPrevenzione
study.

Bpm, beats per minute; CI, confidence interval; RR, relative risk.
Adapted from reference 223: Marchioli R, Avanzini F, Barzi F, et al. Eur Heart J.
2001;22:2085-2103. Copyright © 2001, European Society of Cardiology.

In the PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using InTegrilin) registry of ACS, only limited data were presented regarding heart rate at baseline; median heart rate was 72 bpm (63-80 bpm), but heart rate was significantly associated with clinical events during follow-up, with the effect greater for myocardial infarction than for unstable angina (Figure, page 367).22 The GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico)-Prevenzione study collected data on almost 12 000 patients who had suffered a myocardial infarction in the previous 3 months, and found that a quarter of men and one third of women had a heart rate >75 bpm (Table), which in this study was also associated with an increased risk of subsequent mortality.23

Even when published, for the most part, data from registries of ACS and myocardial infarction patients regarding the resting heart rates encountered in clinical practice are relatively limited. In particular, there is limited information regarding the interrelationship between anti-ischemic and chronotropic medications such as β-blockers or calcium antagonists and the measured heart rate, and no published data on the relationship between resting heart rate and comorbid conditions such as chronic respiratory disease, diabetes, or peripheral vascular disease. Even more importantly, there is no data on the influence of heart rate on subsequent management, the effect of pharmacological interventions on follow-up heart rates, or the effect, if any, of successful heart rate modification on mortality or other outcomes. In effect, there is little data on the control of heart rate in clinical practice.

_ Perioperative heart rate lowering
An exception and important data source on this topic is the literature surrounding β-blockade for the prevention of perioperative cardiac events in vascular surgery patients. Patients undergoing vascular surgery have a high risk of suffering major postoperative cardiac events. This risk can be modified by perioperative β-blockade, although there has been debate in recent years as to the universal benefit of β-blockade in such patients.24

Preoperative myocardial ischemia as detected by Holter monitoring identifies a high-risk subgroup of patients in whom postoperative ischemia, similarly detected, heralds major cardiac events. In one study, Holter monitoring was used to select patients for β-blockade, and it was shown that systematic, patient-specific postoperative heart rate control with β-adrenergic blocker therapy can decrease the incidence of postoperative ischemia among high-risk vascular surgery patients.25 A total of 26 of 150 patients due to undergo elective vascular surgery who were monitored preoperatively by 24-hour Holter monitoring were found to have significant myocardial ischemia defined by ST-segment depression. The ischemic threshold was defined as the minimal heart rate at which this ST-segment depression occurred. These 26 patients were then randomized to receive continuous intravenous βblockade with esmolol or placebo plus usual medical therapy, with the aim of reducing the postoperative heart rate to 20% below the ischemic threshold. All patients were monitored for 48 hours postoperatively. Postoperative Holter readings were analyzed for the incidence of ischemia and for the number of hours during which heart rate was controlled below the ischemic threshold. A total of 15 patients were randomized to receive esmolol, and 11 were randomized to receive placebo. The two groups were comparable with respect to clinical characteristics and incidence and duration of preoperative ischemia. Ischemia persisted in the postoperative period in 8 of 11 placebo patients (73%), but only 5 of 15 esmolol patients (33%) (P<0.05). Of the 15 esmolol patients, 9 had mean heart rates below the ischemic threshold, and all 9 patients had no postoperative ischemia. A total of 4 of 11 placebo patients had mean heart rates below the ischemic threshold, and 3 out of the 4 had no postoperative ischemia. There were two postoperative cardiac events among patients who had postoperative ischemia (one placebo, one esmolol) and whose mean heart rates exceeded the ischemic threshold. These data suggest that patient- specific, strict heart rate control aimed at a predefined target based on the individual preoperative ischemic threshold was associated with a significant reduction and frequent elimination of postoperative myocardial ischemia among highrisk patients.

Figure
Figure. Data from the PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using InTegrilin) registry of ACS.

There was a significant association between heart rate and clinical events during follow-up, with the effect greater for myocardial infarction (MI) than for unstable angina pectoris (UAP). BPM, beats per minute; CI, confidence interval; OR, odds ratio.
After reference 22: Boersma E, Pieper KS, Steyerberg EW, et al; PURSUIT Investigators. Circulation. 2000; 101:2557-2567. Copyright © 2000, American Heart Association, Inc.

In a more recent observational cohort study, 272 vascular surgery patients were preoperatively screened for cardiac risk factors and â-blocker dose, with β-blocker dose expressed as a percentage of the maximum recommended therapeutic dose, and the effect of higher â-blockade and lower heart rate were evaluated.26 β-Blocker dose was converted to a percentage of the maximum recommended therapeutic dose according to the Food and Drug Administration’s Center for Drug Evaluation and Research database. The maximum recommended therapeutic dose for atenolol was 3.330 mg/kg (body weight) per day, for bisoprolol it was 0.330 mg/kg (body weight) per day, for metoprolol 6.670 mg/ kg (body weight) per day, for carvedilol 0.417 mg/kg (body weight) per day, for propranolol 10.700 mg/kg (body weight) per day, and for labetalol 40.700 mg/kg (body weight) per day. Heart rate and ischemic episodes were recorded by continuous 12-lead electrocardiography, starting 1 day before to 2 days after surgery, and serial troponin T levels were measured after surgery. Of the 272 patients, myocardial ischemia was detected in 85 patients (31%) and troponin T release in 44 patients (16.2%). Higher doses of â-blockers were significantly associated with lower heart rates during 12-lead ECG monitoring (78.8 ±11.8, 73.1 ±11.1, and 68.0 ±10.9 bpm in patients with no dose, low-dose, and highdose â-blockers, respectively, P<0.0001), and nonsignificantly associated with lower absolute heart rate change (11.3 ±8.8, 9.6 ±7.2, and 8.5 ±9.7 bpm in patients with no dose, low-dose, and high-dose â-blockers, respectively, P=0.092). In multivariate analysis, higher preoperative heart rates during ECG monitoring (per 10-bpm increase) were significantly associated with an increased incidence of myocardial ischemia (HR, 2.49; 95% CI, 1.79 to 3.48), troponin T release (HR, 1.53; 95% CI, 1.16 to 2.03), and long-term mortality (HR, 1.42; 95% CI, 1.14 to 1.76), with similar patterns observed for intraoperative and postoperative heart rates. This study confirmed that tight heart rate control is associated with reduced perioperative myocardial ischemia, and it further expanded findings by showing that reduced heart rate is also associated with reduced troponin T release and improved long-term outcome in vascular surgery patients.

Following on from such studies, a recent meta-analysis sought to determine the part played by tight heart rate control in the efficacy of perioperative â-blockade. Previous meta-analyses of trials assessing the efficacy of perioperative â-blockade failed to show a consistent reduction in postoperative morbidity and mortality, but showed sizeable heterogeneity of effect, and found that the influence of tight heart rate control had not been considered. The current meta-analysis included 2176 patients from 10 studies, and grouped the trials on the basis of maximal heart rate.27 Trials in which the estimated maximal heart rate was <100 bpm were associated with cardioprotection (odds ratio [OR], 0.23; 95% CI, 0.08-0.65; P=0.005), whereas trials in which the estimated maximal heart rate was >100 bpm did not demonstrate cardioprotection (OR, 1.17; 95% CI, 0.79- 1.80; P=0.43), suggesting that effective heart rate control is important in achieving cardioprotection. Importantly, in the context of the question of heart rate control in clinical practice, 25% of patients receiving â-blockers had episodes during which their heart rate was over 100 bpm, demonstrating that administration of â-blockers does not reliably decrease heart rate in all patients. Furthermore this meta-analysis highlighted the risks of increased side effects, including bradycardia, supporting the judicious use of combination therapy with other drugs to achieve effective postoperative control of heart rate.

_ Heart rate control in stable angina
The area in which data on the control of heart rate in clinical practice is particularly sparse—despite its relevance—is stable angina. Specific questions include those relating to the resting heart rate patterns of patients with stable angina both on and off medication to reduce heart rate, the effects of heart rate on clinical decisions made by cardiologists who are treating patients with stable angina and the clinical scenarios that mediate against tight control of heart rate, the appropriateness of the use of available agents to reduce heart rate, and the effect of appropriate heart rate control on outcome. Studies are emerging, however, that offer to cast light on this important issue.

The Euro Heart Survey on Angina was a prospective, observational, cohort study of patients with stable angina presenting to cardiology services for the first time. Consecutive outpatients with a clinical diagnosis made by a cardiologist were enrolled, and 3779 patients were included in the analysis.28 Patients with stable angina caused by myocardial ischemia secondary to coronary disease were included. The survey was carried out in community-based, ambulatory individuals newly presenting to a cardiologist. The majority of patients had been referred by their primary care physician, with under 10% being self referrals, and the remainder having been referred by general physicians or accident and emergency physicians. Enrolment took place at 197 centers in 36 countries in Europe and the Mediterranean basin.

Although there was marked regional heterogeneity in prescribing patterns, overall, after initial assessment by a cardiologist, 67% of patients were taking (or were recommended to take) a β-blocker, 61% a nitrate, and 27% a calcium channel blocker.29 Most patients (59%) received two or more antianginal drugs, and only 13% received no antianginal therapy. Despite approximately a third of patients taking β-blockers at baseline, the overall mean resting heart rate was 73 bpm.30 Other important points that have been highlighted by this survey are the fact that resting heart rate is affected by comorbid conditions such as chronic respiratory disease and diabetes, with higher resting heart rates recorded in patients with these conditions. β-Blockers are less fre quently prescribed in patients with chronic respiratory disease or diabetes, and crucially, the doses of â-blockade used by both primary physicians and cardiologists were found to be subtherapeutic. These findings clearly point to concern regarding the potential for side effects.

Current treatment options to reduce heart rate chiefly comprise β-blockers and calcium channel blockers,8,9 although selective If channel inhibitors such as ivabradine are a newer addition to the armamentarium.31 Ivabradine was not available at the time of the Euro Heart Survey. While β-blockers are widely prescribed, there are important differences in their pharmacokinetics and pharmacodynamics as well as their side-effect profiles, which will have important effects on tolerability and the maximum prescribed dose,32 all of which need to be considered when targeting heart rate control. The use of combination therapy needs to be judicious and guided by the results of clinical trials, rather than clinical trial and error. The results of the recently published ASSOCIATE trial (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTablockEr), a large trial in over 880 patients, demonstrated that the addition of ivabradine 7.5 mg twice daily to atenolol at the commonly-used dosage in clinical practice in patients with chronic stable angina pectoris, produced additional heart rate reduction. The average heart rate reduction of 9 bpm was significant, allowing the patients to reach the recommended heart rate level of less than 60 bpm. This heart rate reduction was associated with a significant further improvement on all exercise testing parameters, with no untoward effects on safety or tolerability.33

Conclusion

The evidence for targeted heart rate lowering is growing, and there is emerging evidence that a gap exists between guidelines and practice in managing heart rate in the CAD population. The challenge to the cardiology community is twofold: (i) to refine our current knowledge regarding the effect of heart rate lowering on clinical events according to the agents used, the optimal doses, and the specific different clinical presentations of CAD; and (ii) to rapidly translate this evidence into practice. _

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