Heart rate and composite cardiac events: is there a strong association?

Four-year research out of Beijing, China has found bisoprolol to significantly decrease resting heart rate (RHR) in Chinese patients with coronary artery disease (CAD); this lowered the occurrence of composite cardiac events¹. CAD is a major cause of death globally, and the second leading cause of cardiovascular (CV) deaths among the Chinese¹. RHR serves as a physically measurable determinant of oxygen demand, blood flow, myocardial performance and the adaptation of cardiac output to metabolic needs². Heart rate has been established as a biomarker for prognosis of CV outcomes (death, non-fatal acute myocardial infarction and hospitalization for unstable angina)³. Unfortunately, previous reports have shown that heart rate is inadequately controlled by beta-blockers, leading to angina, ischemia and poor general health^4,5. The Reduction of Atherothrombosis for Continued Health study even concluded that beta-blockers were not associated with improving outcomes for patients with stable CAD, but it was the opinion of the study that those findings were due to poor dosage^6,7. Regardless, only a few studies investigated the link between heart rate and CAD in a Chinese population. The present study¹ aimed to increase the information on this topic.

Using bisoprolol, researchers were able to measure a decrease in RHR that was associated with a lower incidence of composite cardiac events⁸. This is promising research for CV patients both in China and globally, but it does not solve the problem outright. More research will need to be conducted regarding the effectiveness of other beta-blockers and higher dosages. Researchers set out to evaluate a change in RHR and its effect on the incidence of cardiac events in Chinese patients with CAD. This single arm observational study was a sub-study of the BISO-CAD trial undertaken across 20 Chinese hospitals between 2011 and 2015. A total of 663 CAD patients with a baseline RHR of 75.47 (±6.62) beats/minute (bpm) were enrolled in the study. Patients older than 20 years of age with stable or unstable angina, as well as diabetes, were enrolled. Data was collected in follow-ups 6, 12 and 18 months after starting the medication.

To begin with, it was found that the risk and frequency of composite cardiac events in patients were significantly increased when a patient had a RHR of 69–74 bpm, especially when compared with those <65 bpm (p = .029)⁸. Most RHRs decreased from their baseline during the study, most notably in the first 6 months of treatment (p ≤ .0001) with an overall baseline value drop from 75.47 (±6.62) to 67.92 (±9.19) bpm⁸. The composite cardiac event rates per group were as follows: 3.23% in the <60 bpm group, 5.41% in the 60–65 bpm group, 7.21% in the 65–70 bpm group, 8.80% in the 70–75 bpm group, 4.00% in the 75–80 bpm group and back up to 8.33% in the 80–85 bpm group. Peculiarly, the event rates fall in the 75–80 bpm group and the 70–75 bpm group has a slightly higher rate of the composite cardiac outcome⁸. It is worth mentioning that in order to achieve the desired statistical power (80% or more) the number of participants in each RHR group will need to be at least doubled. Adverse effects were reported in 146 of the 663 patients. These adverse effects were reported as mild, moderate or severe at a 12%, 7.7% and 3.9% respectively. Of the serious adverse effects, 6 (1%) resulted in death. However, no serious adverse effect was directly related to the study drug⁸. The study also found that there was a 32% increase in total mortality when a patient had a RHR >83 bpm, compared with patients that maintained their RHR under 62 bpm. Patients over 70 years of age and those with diabetes exhibited the most common fatal events⁸. Hospitalization due to acute coronary syndrome (ACS) was significantly higher in patients with higher RHRs (17 events in the 69–74 bpm group vs. 5 events in the <65 bpm group). RHR did not seem to affect coronary revascularization and occurrence of cerebral events⁸.

The BISO-CAD study was one of the first trials to examine the relationship between RHR and clinical outcomes with the use of a selective beta-1 blocker in Chinese patients with CAD. The overall correlation between RHR and risk of CV disease has been studied extensively before. This correlation was found in the general population as well as in patients with ACS, stable CAD and heart failure^9–12. A recent large post hoc analysis investigated the relationship between RHR and CV events in patients with stable CV disease. The study showed that, for each 10 bpm increase in baseline and average RHR, there was a significant increase in risk of CV and all-cause mortality but there was no association between RHR and myocardial infarction¹³. However, in another study, ACS patients after percutaneous coronary intervention with a RHR of >76 bpm were at higher risk of CV events during 1 year follow-up compared to those with RHR between 61 and 76 bpm¹⁴. Further studies have also found the 69–74 bpm RHR group to be the most dangerous group to be in¹⁵.

The bottom line is that there is a significant association between elevated RHR and higher rates of all-cause mortality, CV mortality and CV hospitalization. By now, the pattern is evident: the higher the RHR, the more at risk a patient is for composite cardiac events. Overall, the use of beta-blockers significantly lowered the risk of composite cardiac events in a safe and tolerable way. Despite all of these successes, bisoprolol was not able to achieve the ideal RHR for patients with CAD. Researchers suggest they will need further study with higher doses. Chen et al. used doses of 2.5 and 5 mg; bisoprolol can safely be taken at 10 mg/day, but this will need to be uptitrated gradually to prevent side effects⁸.

However, a study published in 2015 showed that giving a lower dose of a beta-blocker could improve the odds of survival in patients with CV disease¹⁶. Jeffrey Goldberger et al. set out to prove higher doses as used in clinical practice would increase rates of survival, but the results showed the opposite. The data showed that within 2 years: 14.7% died on a full dose; 12.9% died using a half dose; 9.5% died utilizing a quarter dose; and 11.5% died using an eighth dose. This shows a 20–25% decrease in mortality for a patient taking a quarter dose as opposed to a full treatment¹⁶.

Different doses may be required for different patients, so there is no set magic number. It is also possible that there was more mortality in full dose users because they were determined to be at a greater risk of death and therefore received a higher dose. However, patients with a lower dose also benefit from a smaller number of adverse effects such as fatigue, decreased sexual drive and depression. Chen et al.^1,8 only tested bisoprolol, one of many beta-blockers; others should also be evaluated. More studies should carefully monitor whether a high dosage of a beta-blocker continues to push the RHR down to standard safe numbers, instead of plateauing after 6 months. These studies also need to correlate that effect with the incidence of composite cardiac events in patients with CV disease.

Transparency

Declaration of funding

This commentary was not funded.

Declaration of financial/other relationships

A.I. and T.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO Editorial Board peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

None reported.