Abstract
Phase 2 cardiac rehabilitation (CR) employs evidenced‐based interventions to modify the risk of cardiac morbidity in its participants. The prevalence of apparent treatment‐resistant hypertension (aTRH) among CR participants is unknown. A retrospective analysis of a longitudinal cohort of patients who completed CR between 2012 and 2017 was undertaken. The prevalence of hypertension was 62% (n = 311). 11% of participants with hypertension had aTRH (n = 35). Participants with aTRH exhibited lower exercise capacity (EC) before starting CR and after its completion compared to normotensive counterparts (P < .001). aTRH participants were more likely to experience a decrease in EC, even after participating in cardiac rehabilitation, compared to normotensive participants (P = .02). aTRH participants were more likely to be hospitalized or seen in the emergency department after cardiac rehabilitation completion compared to normotensive counterparts (OR: 2.85, P < .01). CR presents an opportunity to identify and appropriately care for patients with aTRH.
Keywords: cardiac rehabilitation, exercise capacity, hypertension, resistant hypertension
1. INTRODUCTION
Phase 2 cardiac rehabilitation (CR) is a medically supervised exercise and educational program comprising 36 sessions. Enrollment in CR is a Class 1 recommendation following cardiac surgery (including valve repair/replacement or coronary artery bypass grafting,) percutaneous coronary intervention, myocardial infarction, or cardiac transplantation. CR is also recommended for patients with stable angina or those with chronic heart failure, with a left ventricular ejection fraction equal to or <35%. 1 CR presents an opportunity to identify individuals at high risk for recurrent cardiovascular events and to intensify treatment of cardiovascular risk factors such as hypertension. Patients with apparent treatment‐resistant hypertension (aTRH) are one such group that is at high risk for cardiovascular disease. 2
The overall prevalence of aTRH among patients with known hypertension is 12%‐20%. 3 , 4 , 5 By definition, these are patients who demonstrate an above goal, elevated blood pressure (BP) despite taking 3 antihypertensive medications commonly including a long‐acting calcium channel blocker, a blocker of the renin‐angiotensin system, and a diuretic, all administered at maximum or maximally tolerated daily doses. 3 In select patients, BP may be controlled using a regimen involving 4 antihypertensive medications, and these individuals are classified as exhibiting controlled aTRH.
With over a million CR qualifying events occurring in the United States every year, 6 CR presents an opportunity to improve clinical management of cardiovascular comorbidities, including hypertension. Better understanding the prevalence of aTRH in this patient population serves to improve BP control and avail patients of the most up to date treatment paradigms.
The present study is a single‐center retrospective analysis of a longitudinal cohort of CR participants, performed to determine the prevalence of aTRH among all CR participants and CR participants with hypertension. The authors also sought to assess if CR participants with aTRH demonstrate an increased risk of adverse clinical outcomes compared to CR participants without aTRH. Additionally, the study aimed to assess if CR participants with aTRH had similar improvements in exercise capacity (EC) via participation in CR compared to participants without aTRH.
2. METHODS
Five‐hundred and four consecutive patients who completed CR at the main campus of the Cleveland Clinic in Cleveland, Ohio, USA were evaluated between 2012 and 2017. Baseline demographics, vital signs, comorbidities, and medications were assessed via review of electronic medical records. Exercise stress testing was performed before starting and after completion of CR. EC was defined as peak metabolic equivalents (METs) and estimated via symptom limited exercise stress testing. Treadmill protocols included Bruce, Cornell, Cornell 2.0, Naughton, or modified Naughton. Upright bicycle protocols included 1‐minutes step‐wise increases in Watts estimated so that tests lasted 8‐12 minutes. Clinical outcomes including mortality (up to 5 years following completion of CR) and first occurrence of a hospitalization or emergency department visit (for the 2 years following completion of CR) were determined by electronic medical record review. The electronic medical record is linked to the social security death index and includes data from all hospitals within the Cleveland Clinic Health System in the United States.
Baseline resting BP measurement was performed per clinic protocol with a brachial oscillometric machine. Participants were identified as aTRH if they had a known diagnosis of hypertension at the time of CR enrollment, were taking 3 or more antihypertensive medications, of which one was a diuretic, and had a resting systolic BP >130 mm Hg. If known hypertensive participants were taking 4 or more antihypertensive medications, they were also identified as aTRH, irrespective of BP.
Cardiac rehabilitation participants with aTRH were compared to participants with non‐resistant hypertension, and those without hypertension (normotensive). The primary outcome of interest was the prevalence of aTRH among CR participants. Secondary outcomes included EC upon CR enrollment and completion, as well as differences in 5‐year survival and hospitalizations in the 2 years following CR.
2.1. Statistical analyses
Continuous data are presented as means (standard deviation) and categorical data as percentages. Baseline variables between all groups were compared using the Kruskal‐Wallis test for continuous variables (with post hoc Dunn's testing), and using the Fisher exact test for categorical variables. Multivariable logistic regression testing was performed to correct for factors found to be associated with outcomes of interest on univariate analysis with a P < .10. Variables considered for the logistic models included age, race, sex, body mass index, and the presence of heart failure with reduced ejection fraction, atrial fibrillation, diabetes mellitus, hyperlipidemia, stage 3 chronic kidney disease or higher, and peripheral arterial disease. Variables included in the regression models include age, race, body mass index, presence of heart failure with reduced ejection fraction, presence of atrial fibrillation, presence of chronic kidney disease, and presence of peripheral arterial disease. Statistical significance was defined as P < .05. Analysis was performed using Stata 15.1 (StataCorp LP). Informed consent was obtained from all CR participants. The present study was approved by the IRB of the Cleveland Clinic (Study # 18‐1260).
3. RESULTS
The prevalence of aTRH among CR participants with hypertension was 11.3% (95% CI, 8.0%‐15.3%). Among all CR participants, 6.9% (95% CI, 4.9%‐9.5%) had aTRH and 54.7% (95% CI, 50.3%‐59.2%) had non‐resistant hypertension. Participants with aTRH were older, more likely to be non‐white, and have cardiovascular comorbidities (all P < .01) (Table 1). Individuals with aTRH exhibited lower exercise capacity (EC) at CR entry compared to both non‐resistant hypertensive and normotensive counterparts (P = .04 and P < .001 respectively) and lower EC at CR completion compared to normotensive CR participants (P < .001) (Table 2). Participants with aTRH were also more likely to experience a decrease in EC, even after participating in CR (14.3%, OR 4.08, P = .02), compared to normotensive participants (3.6%, reference).
Table 1.
Demographic factors of cardiac rehabilitation participants by hypertensive status
| Normotensive (NT) (n = 193) | Non‐resistant hypertension (HTN) (n = 276) | Resistant hypertension (aTRH) (n = 35) | P‐value a aTRH vs HTN vs NT | P‐value a aTRH vs NT | P‐value a aTRH vs HTN | |
|---|---|---|---|---|---|---|
| Age [years (SD)] | 55.0 (14.7) | 62.8 (10.2) | 65.1 (9.6) | <.001 | <.001 | .15 |
| Race (% Caucasian) | 61.1% | 42.0% | 25.7% | <.001 | <.001 | .03 |
| Male [%] | 76.2% | 69.6% | 57.1% | .05 | .01 | .06 |
| Type 2 diabetes mellitus [%] | 16.6% | 35.9% | 54.3% | <.001 | <.001 | .01 |
| Hyperlipidemia [%] | 61.1% | 85.5% | 80.0% | <.001 | .01 | .23 |
| BMI [kg/m2 (SD)] | 27.0 (4.6) | 29.7 (6.1) | 31.4 (6.7) | <.001 | <.001 | .09 |
| HFrEF (LVEF < 50%) [%] | 20.2% | 22.8% | 34.3% | .19 | .03 | .06 |
| Atrial fibrillation [%] | 29.5% | 30.8% | 31.4% | .94 | .41 | .47 |
| CKD [%] | 16.5% | 31.2% | 19.2% | <.001 | .39 | .09 |
| Peripheral arterial disease [%] | 9.3% | 10.9% | 17.1% | .36 | .08 | .13 |
| CAD as indication for CR b | 45.0% | 72.8% | 57.1% | <.01 | .10 | .04 |
Abbreviations: BMI, body mass index; CAD, Coronary artery disease; CKD, Chronic kidney disease Class 3a or greater; CR, cardiac rehabilitation; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; SD, Standard deviation.
Kruskal‐Wallis (with post hoc Dunn's testing for pairwise comparison where appropriate), or Fisher's exact test.
This includes angina, percutaneous coronary intervention, non‐st elevation myocardial infarction, st elevation myocardial infarction, or coronary artery bypass grafting.
Table 2.
Resting blood pressure and peak metabolic equivalents achieved during exercise stress testing upon entry and exit from cardiac rehabilitation sorted by hypertensive status
| Normotensive (NT) | Non‐resistant hypertension (HTN) | Resistant hypertension (aTRH) | P‐value a aTRH vs HTN vs NT | P‐value a aTRH vs NT | P‐value a aTRH vs HTN | |
|---|---|---|---|---|---|---|
| Enrollment in cardiac rehab SBP [mmHg (SD)] | 117 (15) | 127 (19) | 137 (17) | <.001 | <.001 | <.001 |
| Enrollment in cardiac rehab DBP [mmHg (SD)] | 76 (11) | 78 (12) | 80 (11) | .07 | .02 | .12 |
| Completion of cardiac rehab SBP [mmHg (SD)] | 117 (12) | 128 (17) | 129 (17) | <.001 | <.001 | .30 |
| Completion of cardiac rehab DBP [mmHg (SD)] | 77 (9) | 79 (10) | 79 (10) | .23 | .23 | .44 |
| Peak METs enrollment in cardiac rehab [Mean (SD)] | 7.62 (2.70) | 6.15 (2.46) | 5.34 (2.14) | <.001 | <.001 | .04 |
| Peak METs completion of cardiac rehab [Mean (SD)] | 9.64 (2.65) | 7.70 (2.90) | 6.80 (2.62) | <.001 | <.001 | .08 |
Abbreviations: DBP, diastolic blood pressure; METs, metabolic equivalents; SBP, systolic blood pressure; SD, Standard deviation.
Kruskal‐Wallis (with post hoc Dunn's testing for pairwise comparison where appropriate), or Fishers exact testing.
65.7% (23 of 35) of aTRH CR participants were hospitalized or seen in the emergency department in the 2 years following completion of CR. When controlling for differences in risk factors for cardiovascular disease, aTRH individuals were more likely to be hospitalized or seen in the emergency department compared to normotensive participants (OR: 2.85, P < .01). Participants with non‐resistant hypertension demonstrated a similar increased risk of hospitalization or emergency department visit (OR: 1.86, P < .01). Up to 5 years following completion of CR, 4 of 193 normotensive participants died (2.1%, reference), compared to 6.5% (OR: 2.23, ns) of participants with non‐resistant hypertension and 5.7% of participants with aTRH (OR 0.87, ns), (Table 3).
Table 3.
Risk‐adjusted outcomes of patients with resistant hypertension participating in cardiac rehabilitation
|
Normotensive (NT) (n = 193) |
Non‐resistant hypertension (HTN) (n = 276) |
Resistant hypertension (aTRH) (n = 35) |
|
|---|---|---|---|
| Death [% (n) [OR {95%C}]] |
2.1% (4) [Ref] |
6.5% (18) [2.23 {0.57‐8.69}] |
5.7% (2) [0.87 {0.10‐7.52}] |
| Hospitalizations or ED visit [% (n) [OR {95%CI}]] |
36.8% (71) [Ref] |
54.4% (150) [1.86 {1.21‐2.86}]** |
65.7% (23) [2.85 {1.25‐6.52}]** |
| Participants with a decrease in EC after completing CR [% (n) [OR {95%CI}]] |
3.6% (7) [Ref] |
9.8% (27) [2.85 {1.21‐6.71}]* |
14.3% (5) [4.08 {1.20‐13.87}]* |
Abbreviations: CR, cardiac rehabilitation; EC, exercise capacity; Ref, reference.
P = .02.
P < .01.
4. DISCUSSION
The prevalence of aTRH among all adults in the United States treated for hypertension varies based on the population sampled and BP thresholds used to define aTRH. The prevalence of aTRH in population‐based studies of patients with hypertension is between 12% and 15%, and in clinic‐based studies approximately 15%‐18%. 3 The 11% prevalence of aTRH among hypertensive CR participants reported herein is well in‐line with these estimates. The prevalence of aTRH among all United States adults is estimated at 8.9%, whereas the prevalence of aTRH in the CR population was lower at 6.9%. 7 The demographic correlates within the CR cohort with aTRH are consistent with prior findings, including an increased likelihood of being non‐white, older age, and a higher likelihood of cardiovascular comorbidities including obesity and diabetes mellitus. 8 , 9 , 10 One potential reason for the lower aTRH prevalence among CR participants compared to previous estimates is that CR participants are less likely to have pseudoresistant hypertension. Given that these individuals recently had a major operation or adverse cardiovascular event, they are likely more adherent to medications and there is less treatment inertia on the part of the treating physician. 11
Upon starting and completing CR, participants with aTRH demonstrate decreased EC compared to both normotensive and non‐resistant hypertension counterparts. Although the majority of aTRH participants improved EC during CR, a larger percentage of aTRH participants did not improve their EC by partaking in CR (14.3%), when compared with normotensive individuals (3.6%). The effect of exercise training on patients with aTRH has been examined previously, although not specifically in the CR setting, and not in direct comparison to non‐resistant hypertensive individuals. 12 , 13 These studies examine the effect of exercise programs on BP, but not exercise or clinical outcomes. Unsurprisingly, the data demonstrate significant BP reductions with exercise training up to 12 weeks. Why CR participants with aTRH did not improve their EC as much as other CR participants is not clear, and given the relative paucity of data with respect to physical activity and aTRH, more investigation is required. 3
When controlling for cardiovascular comorbidities, aTRH is a significant risk factor for hospitalization or emergency department visits compared to normotensive counterparts enrolled in CR. The increased morbidity associated with a diagnosis of aTRH is consistent with prior studies. 14 , 15 There was no significant difference in mortality following CR completion in aTRH or non‐resistant hypertensive patients compared to normotensive participants, though this work was not powered to detect such a difference.
Limitations of the current study include assessing the prevalence of true resistant hypertension is challenging given the need to confirm medication adherence and out‐of‐office BP measurements. Confirmatory testing was not available in this longitudinal cohort and thus the term aTRH must be used. Notably, patients were excluded from the aTRH cohort if their medical record specifically noted a diagnosis of white coat hypertension or white coat effect. Limitations of BP measurement outside of a clinical trial setting are clearly present as well, although standard resting office measurement protocols are used according to published guidelines.
This work represents the first description of the prevalence of aTRH in the CR population while also demonstrating these individuals are at high risk for adverse outcomes. The foundation of knowledge provided by this study highlights the importance of this group of patients and identifies aTRH as a potential treatment target in CR programs.
CONFLICT OF INTEREST
Dr Laffin is a member of the Hypertension Eligibility Committee for Vascular Dynamics’ CALM‐2 trial. Other authors have no conflicts to report.
ACKNOWLEDGMENTS
The authors thank Michael R. Laffin for manuscript review.
Laffin LJ, Khan A, Lang K, Van Iterson EH. Prevalence and clinical outcomes of patients with apparent treatment‐resistant hypertension enrolled in Phase 2 cardiac rehabilitation. J. Clin. Hypertens. 2020;22:2377–2381. 10.1111/jch.14057
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