We investigated associations between baseline and follow-up RHR and adverse outcomes in elderly hypertensive patients with chronic CAD using the INVEST population. We found both RHR variables were associated with adverse outcomes with a linear relationship for baseline RHR and a J-shaped relationship for follow-up RHR. The novelty of our investigation is that the results were obtained in a population of treated patients with excellent BP control and also that follow-up RHR, using two different RHR-lowering treatment strategies, was tested as a predictor of adverse outcomes. Most studies on the clinical role of RHR have been carried out in untreated and different populations and in the limited data available (e.g. Syst-Eur study)18
no relationship of RHR with outcome was found with treatment.
Our findings support and extend previous epidemiological and clinical studies, showing that increased RHR is associated with increased risk in patients with isolated systolic hypertension (ISH),10
acute coronary syndromes,26 – 28
The increased risk that we observed was at an RHR as low as 75 b.p.m., well below the definition of tachycardia. Consistency of this observation across different risk levels suggests that increased RHR is a marker of additional risk. In our treated hypertensive CAD patients, elevated baseline and follow-up RHR were associated with an increasing risk for adverse outcomes consistent with findings from untreated elderly patients in the Syst-Eur trial18
and patients with CAD and hypertension in the Coronary Artery Surgery Study (CASS) registry.31
These earlier studies suggested that RHR >75 and >77 b.p.m., respectively, were associated with increased risk of all-cause death18,31
and >83 b.p.m. for cardiovascular death.31
In our study, the association with increased risk is apparent with mean follow-up RHR >75 b.p.m. within both treatment strategies (), whereas in the adjusted follow-up RHR model the nadir was 59 b.p.m.
Reports are conflicting as to whether the direct relationships between RHR and cardiovascular death or all-cause death are linear across the RHR range, or if risk becomes also increased at relatively low RHR (i.e. J-shaped).16,18,26,27,31,32
Generally, studies of high-risk patients (e.g. with comorbidities such as ISH, unstable angina/non-ST-elevation MI) and men after acute MI have suggested a J-shaped relationship between RHR and all-cause death.18,26,27
In support of these suggestions, the J-curve relationship between risk of adverse outcomes and mean follow-up RHR that we observed is slightly more pronounced in the diabetes () and prior MI () subgroups. It is unclear whether this increased risk at lower RHR may be directly related to underlying CAD severity or associated with unrecognized factors related to CAD. On the other hand, it should be pointed out that the upturn in the relationship was due to a small number of subjects (and events) in the lower RHR groups and that the upturn is more evident in the subgroup with prior MI. The linear relationship between risk of adverse outcomes and baseline RHR observed here is consistent with recent findings from other patients with CAD.31
However, in our analysis baseline RHR was not a significant predictor of adverse outcomes when included in the same model with mean follow-up RHR, suggesting that on treatment RHR contributes more information to the prediction of adverse outcomes. This has relevance to the report from the Syst-Eur trial,18
where on treatment RHR was not associated with adverse outcomes but BP was much higher than in the INVEST.
Our study is one of few examining the relationship between RHR reduction and outcomes in treated patients. Although both treatment strategies reduced RHR, mean RHR at 24 months was significantly lower in the At strategy than in the Ve strategy. Despite previous studies showing a relationship between the degree of β-blocker heart rate lowering and outcome, there was no difference in outcome between the two treatment strategies either in the entire cohort or in the higher risk post-MI, diabetes, or gender subgroups. This observation suggests that verapamil may have additional beneficial effects beyond reduction of RHR by calcium antagonist activity at the sinus node. One possible explanation may relate to a sympatholytic effect,33
as verapamil lowers catecholamine levels whereas β-blockers increase such levels. Additionally, all calcium antagonists are potent coronary arteriolar dilators.
Analyses of high-risk subgroups with diabetes or previous MI yielded similar results in terms of outcome and relationship with mean follow-up RHR. As previously reported,25
the equivalence in clinical outcomes between the Ve and At strategies overall is especially remarkable considering the post-MI subgroup where β-blockers are standard for care for secondary prevention. Our data are consistent with the DAVIT II,34
and other studies,36
where beneficial effects of verapamil-SR were established in CAD patients with and without a history of prior MI and/or hypertension. In our prior MI subjects, the adverse outcome nadir was observed at a higher follow-up RHR than for the entire cohort (64 vs. 59 b.p.m.). The higher follow-up RHR nadir was consistent with the higher risk for adverse outcomes observed in these prior MI subjects. This may reflect autonomic compensation for limited cardiac performance as a result of prior MI that may begin before overt HF. Our report provides new information on RHR response by gender. For the same BP control, men and women had higher follow-up mean RHR with the Ve than with the At strategy, although no difference in clinical outcome was detectable. Consistent with previous studies,14,16,31
women had a higher RHR than men, independent of treatment or comorbidities. Prior studies have suggested that the relationship between RHR and all-cause mortality is weaker in women than in men and that a higher RHR is a weak predictor of cardiovascular death in women.17
Therefore, the high RHR in women may simply represent the extreme of normal distribution. Our results suggest that the predictive value is the same, but from a different (higher) reference RHR. In this elderly patient population with hypertension and CAD, for the same RHR, males have a greater risk of adverse outcomes.
When interpreting this analysis, one must consider its limitations. There is potential for selection bias when using controlled clinical trial instead of epidemiological cohorts. However, INVEST enrolled over 22 000 patients with hypertension and CAD and applied very few exclusion criteria (acute events and contraindications to study medications) that biased baseline demographics.25
The INVEST population can be considered as all inclusive for stable CAD patients 50 and older who are candidates for either β-blocker or heart-rate-slowing calcium antagonist treatment. Also, there were relatively few patients and events at the lowest RHR levels, particularly in the subgroup analyses, and the results are specific to the study drugs and not to their respective drug classes. The role of β-blockers, in general, and particularly, atenolol in treatment of primary hypertension has recently been called into question.37,38
However, in the INVEST, both the Ve and the At treatment strategies were similarly effective in BP control in a CAD population (at 24 months, 71.7% of Ve strategy patients and 70.7% of At strategy patients had BP below 140/90 mmHg).25
This was likely related to use of twice daily atenolol dosing when the dose exceeded 50 mg/day as in most of the INVEST patients,25
but was not the case for many prior hypertension trials.