Cardiac Rehabilitation for Patients With Stable Ischemic Heart Disease Without Revascularization　― Rationale and Design of a Single-Arm Pilot Study ―

Abstract

Background: Clinical practice guidelines strongly recommend optimal medical therapy (OMT), including lifestyle modification, pharmacotherapy, and exercise-based cardiac rehabilitation (CR), in patients with stable ischemic heart disease (SIHD). However, the efficacy and safety of CR in patients with SIHD without revascularization remain unclear.

Methods and Results: The Prospective Registry of STable Angina RehabiliTation (Pre-START) study is a multicenter, prospective, single-arm, open-label pilot study to evaluate the efficacy and safety of CR on health-related quality of life (HRQL), exercise capacity, and clinical outcomes in Japanese patients with SIHD without revascularization. In this study, all patients will undergo guideline-based OMT and are encouraged to have 36 outpatient CR sessions within 5 months after enrollment. The primary endpoint is the change in the Seattle Angina Questionnaire-7 summary score between baseline and the 6-month visit; an improvement of ≥5 points will be defined as a clinically important change. Secondary endpoints include changes in other HRQL scores and exercise capacity between baseline and the 6-month visit, as well as clinical outcomes between enrollment and the 6-month visit.

Conclusions: The Pre-START study will provide valuable evidence to elucidate the efficacy and safety of CR in patients with SIHD and indispensable information for a subsequent randomized controlled trial. The study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (ID: UMIN000045415) on April 1, 2022.

Recently, some randomized control trials (RCTs) showed that percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) did not decrease cardiovascular events in patients with stable ischemic heart disease (SIHD),^1,2 and subsequent meta-analyses confirmed these results.^3–6 As a result, the 2021 American College of Cardiology/American Heart Association clinical practice guideline restricted the indication of PCI for SIHD in patients with left main stenosis, a multivessel disease with a reduced left ventricular function, or refractory angina symptoms despite anti-anginal drugs.⁷

Guidelines also recommend optimal medical therapy (OMT), including lifestyle modification and pharmacotherapy, for event prevention and symptom relief.^7–9 However, the details of “optimal” medical therapy, especially lifestyle modification, remain controversial. Usually, lifestyle modification includes smoking cessation, a healthy diet, physical activity, weight control, and psychological management.

In addition, guidelines strongly recommend exercise-based cardiac rehabilitation (CR) in patients with various heart diseases.^7,8,10 In particular, the Japanese Circulation Society/the Japanese Association of Cardiac Rehabilitation recently upgraded CR for patients with SIHD (class I, level of evidence B).¹⁰ CR is a comprehensive intervention for patients with heart disease, including supervised or unsupervised exercise training, health education, and counseling for cardiovascular risk reduction.¹¹ These recommendations are based on systematic reviews showing that CR reduced cardiac death in patients with ischemic heart disease.¹² However, evidence about CR in patients with SIHD is scarce because most of the patients in these studies were taking part in CR after acute myocardial infarction or revascularization, and few patients with SIHD were included. For example, a systematic review of CR for SIHD found that CR slightly improved exercise capacity but did not reduce cardiac events such as death, myocardial infarction, or hospitalization.¹³

Conversely, although health-related quality of life (HRQL) has been recognized as an important outcome, it is still underused.¹⁴ Some systematic reviews have shown that CR improves HRQL, such as the 36-Item Short Form Survey Instrument and the MacNew Heart Disease Questionnaire.^15–17 However, although some RCTs showed that CR improved HRQL in patients with SIHD, no study has exclusively included patients without revascularization. Thus, the efficacy and safety of CR on HRQL in patients with SIHD with OMT but without revascularization remain unclear.

Therefore, we aim to evaluate: (1) the efficacy and safety of CR on HRQL, exercise capacity, and clinical outcomes; and (2) the feasibility of an RCT in patients with SIHD without revascularization.

Methods

The Prospective Registry of STable Angina RehabiliTation (Pre-START) study is a multicenter, prospective, single-arm, open-label pilot study in Japan. Ethics approval will be obtained at each participating institution or the Kyoto Prefectural University of Medicine Ethics Committee. The study will be conducted in accordance with the Declaration of Helsinki. Written informed consent will be obtained from all patients. The study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (ID: UMIN000045415) on April 1, 2022.

Eligibility Criteria

All inclusion and exclusion criteria are presented in Table 1. Briefly, patients aged ≥20 years; those with angina symptoms with Canadian Cardiovascular Society (CCS) classification I–III or asymptomatic and those with documented myocardial ischemia or significant coronary artery stenosis among major coronary arteries will be eligible for inclusion. The following patients will be excluded: those with an acute coronary syndrome, including CCS class IV unstable angina; those with 3-vessel or left main disease; those admitted for myocardial infarction or those who underwent coronary artery revascularization within the 6 months; those with a left ventricular ejection fraction <35%; those with a history of heart failure, pulmonary hypertension, valvular heart disease, dilated or hypertrophic cardiomyopathy, aortic aneurism, or severe kidney disease; those with a cardiac implantable electronic device; and or those with a contraindication to aspirin.

Table 1. Eligibility Criteria

Inclusion criteria

Patients must fulfill the following:

1. Willing to provide written informed consent

2. Age ≥20 years

3. Have angina symptoms with CCS classification I–III or asymptomatic myocardial ischemia

4. Have ≥10% myocardial ischemia on myocardial perfusion scintigraphy or significant coronary artery stenosis (>90% stenosis or >50% stenosis with positive results in fractional flow reserve [<0.8] or resting indices [<0.89]A) among major coronary arteries on invasive coronary angiography

Exclusion criteria

1. Acute coronary syndrome, including unstable angina with CCS classification IV

2. Three-vessel coronary artery disease

3. Left main coronary artery disease

4. Myocardial infarction within 6 months

5. Coronary artery revascularization within 6 months

6. Contraindication to aspirin

7. Left bundle branch block or Wolff-Parkinson-White syndrome

8. NYHA class III–IV heart failure at entry or hospitalization for exacerbation of heart failure within 6 months

9. Reduced left ventricular ejection fraction <35%

10. Pulmonary hypertension requiring drug therapy

11. Moderate or severe valvular heart disease or previous surgical/percutaneous treatment for valvular heart disease

12. Dilated or hypertrophic cardiomyopathy

13. Moderate or severe aortic aneurysm

14. Cardiac implantable electronic device including pacemaker, implantable cardioverter defibrillator, or biventricular pacemaker implantation

15. Left or right ventricular assist device or heart transplantation

16. Unable to exercise due to musculoskeletal disease or peripheral arterial disease

17. Terminal illness

18. Pregnant or lactating women

19. Estimated glomerular filtration rate <30 mL/min/1.73 m2, maintenance dialysis, peritoneal dialysis, or post-renal transplantation

20. Home is far away from an outpatient cardiac rehabilitation center

21. Participating in another clinical trial involving interventions

22. Treating physician judged it inappropriate to participate in the study

23. Do not understand the Japanese language

24. Study researchers and their family members

^AResting indices include instantaneous wave-free ratio, diastolic pressure ratio, diastolic hyperemia-free ratio, and resting full-cycle ratio. CCS, Canadian Cardiovascular Society; NYHA, New York Heart Association.

Baseline Assessment

Each patient will undergo the following at baseline: recording of baseline characteristics such as age, sex, body mass index, vital signs, previous history, and comorbidities; laboratory studies; electrocardiogram (ECG); echocardiogram; CCS classification; HRQL assessment using the Seattle Angina Questionnaire (SAQ)-7 and 12-Item Short Form Survey Instrument (SF-12); psychological assessment using the Hospital and Anxiety Depression Scale (HADS); physical activity using metabolic equivalent of tasks (METs) per week; cardiopulmonary exercise test (CPX); and myocardial ischemia and coronary artery stenosis (Figure).

Figure.

Schedule of enrollment, intervention, and assessments. –1, before enrollment; 0, time of enrollment. CCS, Canadian Cardiovascular Society; CPX, cardiopulmonary exercise test; ECG, electrocardiogram; HADS, Hospital and Anxiety Depression Scale; SAQ-7, Seattle Angina Questionnaire-7; SF-12, 12-Item Short Form Survey Instrument.

Coronary artery stenosis will be evaluated by coronary computed tomography angiography if a patient has ≥10% myocardial ischemia on myocardial perfusion scintigraphy or invasive coronary angiography otherwise. Significant coronary artery stenosis is defined as >90% angiographical stenosis or >50% with positive results in fractional flow reserve or resting indices in major coronary arteries (Table 1).

CPX (ramp protocol using a bicycle ergometer) will be used to evaluate symptoms, ECG changes, arrhythmia, blood pressure, heart rate response, and exercise capacity. During CPX, patients will be encouraged to achieve a peak respiratory exchange ratio (RER) of ≥1.1 or prespecified exercise-stopping criteria. The following parameters will be measured through CPX: oxygen consumption (V̇O₂); anaerobic threshold (AT), determined by the V slope method; peak work rate (WR); V̇O₂ and WR at ≥1 mm ST depression; the slope of minute ventilation (V̇E) vs. carbon dioxide output (V̇CO₂); minimum V̇E/V̇CO₂; and RER. WR 1 min before AT is used for exercise prescription.¹⁸

Lifestyle Modification and OMT

All patients will receive guideline-based OMT, including lifestyle modification and pharmacotherapy. Therapeutic targets are as follows: systolic blood pressure <130 mmHg, low-density lipoprotein cholesterol (LDL-C) <100 mg/dL, body mass index <25 kg/m², and HbA1c <7.0%. Lifestyle counseling will be conducted using an original pamphlet that includes the following: smoking cessation, aerobic exercise for >30 min per 3–7 days per week, healthy diet, weight control, and stress management.

Pharmacotherapy targets symptom relief and event prevention. The following anti-anginal drugs will be used for symptom relief. First, monotherapy with β-blockers or calcium channel blockers is administered. Then, if symptoms persist, both a β-blocker and calcium channel blockers are used. Finally, long-acting nitrates or nicorandil will be added if symptoms persist under combination therapy. Drugs for event prevention include the following: antiplatelet agents, including 81–100 mg/day aspirin and P2Y₁₂ inhibitors if necessary; strong statins, such as 2–4 mg pitavastatin, 10–20 mg atorvastatin, or 5–10 mg rosuvastatin at the highest dose; ezetimibe if statins are contraindicated, poorly tolerated, or LDL-C does not reach <100 mg/dL with the maximum dose of statins; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers for patients with an estimated glomerular fraction rate <60 mL/min/1.73 m² or diabetes; and β-blockers for patients with a history of myocardial infarction.

Exercise-Based CR

In this study, all patients will undergo exercise-based CR. Each patient will be encouraged to complete 36 supervised CR sessions within 5 months. A bicycle ergometer is allowed for the aerobic exercise training modality. Whether and how to implement resistance training is left to the discretion of the attending physician. No other forms of exercise (e.g., treadmill walking, upper extremity ergometers, dancing, water exercise, or high-intensity interval training) are allowed. Each exercise session will consist of 5–10 min of warm up, 20–40 min of aerobic exercise (±resistance) training, and 5–10 min of cool down.

The initial aerobic exercise intensity is based on the AT determined by CPX. If the AT is difficult to determine, exercise intensity is determined based on heart rate and exercise intensity at 40–60% of peak V̇O₂. If the angina is stable, exercise intensity can be increased to a goal of 12–13 subjective exercise intensity (Borg index).

Coronary Revascularization

Coronary revascularization can be performed in case of acute coronary syndrome including unstable angina, intolerable anginal symptoms with at least 2 anti-anginal drugs, or at the patient’s request. The type of revascularization (PCI or CABG) and management are left to the discretion of the attending physician or local heart team.

Endpoints

Follow-up is started at the first CR session, scheduled at 3 and 6 months (Figure). The primary endpoint is the change in the SAQ-7 summary score between baseline and the 6-month visits. Secondary endpoints include changes in HRQL scores and exercise capacity between baseline and the 6-month visits, as well as clinical outcomes between enrollment and the 6-month visits. HRQL scores other than the primary outcome include changes from baseline values in SAQ-7 subscales (physical limitation, angina frequency, and quality of life); 3 summary scores (physical component summary, mental component summary, and role/social component summary) and 8 subscales (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health) of the SF-12; and 2 summary scores of the HADS (HADS-Depression, HADS-Anxiety). Exercise capacity includes peak V̇O₂, AT, peak WR, and exercise time to ≥1-mm ST-segment depression. Clinical outcomes include the composite outcome of all-cause mortality and myocardial infarction, all-cause mortality, cardiac death, non-fatal myocardial infarction, coronary revascularization (PCI or CABG), and hospitalization for heart failure (Table 2).

Table 2. Endpoints

Primary endpoint

Change in the SAQ-7 summary score at 6 months

Secondary points

1. Change in SAQ-7 subscales (physical limitation, angina frequency, and quality of life) at 6 months

2. Changes in the 3 summary scores of the SF-12 (physical component summary, mental component summary, and role/social component summary) at 6 months

3. Changes in the 8 subscales of the SF-12 (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health) at 6 months

4. Changes in the 2 summary scores of the HADS (HADS-Depression, HADS-Anxiety) at 6 months

5. Exercise capacity (peak V̇O2, AT, peak WR, exercise time to ≥1-mm ST-segment depression) at 6 months

6. Composite of all-cause death and non-fatal MI

7. All-cause mortality

8. Cardiac death

9. Non-fatal MI

10. Hospitalization for heart failure

11. Coronary revascularization (PCI or CABG)

AT, anaerobic threshold; CABG, coronary artery bypass grafting; HADS, Hospital and Anxiety Depression Scale; MI, myocardial infarction; PCI, percutaneous coronary intervention; SAQ-7, Seattle Angina Questionnaire-7; SF-12, 12-Item Short Form Survey Instrument; V̇O₂, oxygen consumption; WR, work rate.

Statistical Analysis

Sample Size Calculation Because this is a pilot study, formal sample size calculation was not performed. However, we will include 50 patients because this will be enough to check the feasibility of the subsequent RCT and estimate the change in HRQL in this population.

Primary Statistical Analysis The primary endpoint, an improvement of ≥5 points in the SAQ-7 summary score from baseline, is defined as the clinically important change. The number and proportion of patients who achieved the cut-off will be reported and tested using a Chi-squared test. In addition, changes in HRQL scores and exercise capacity from baseline will be tested using paired t-tests or the Wilcoxon signed rank-sum test according to data distribution. For cardiovascular events, Kaplan-Meier plots will be generated for cumulative events, log-rank tests will be performed, and the Cox proportional hazards model will be used to estimate hazard ratios and 95% confidence intervals. For missing values, a complete case analysis will be planned as the main analysis, and the multiple imputation method will be used as a sensitivity analysis. In addition, the following predefined subgroup analyses will be conducted (all other subgroup analyses will be post hoc analyses): the presence of ≥1-mm ST-segment depression on baseline exercise stress ECG with CPX; and angina frequency in the baseline SAQ (none in the past 4 weeks or others). All tests are 2-tailed with a significance level of 5%. Statistical analyses will be performed using the statistical programming language R, version 4.2.1 or higher.

Summary and Significance

Guidelines strongly recommend exercise-based CR because it reduces morbidity and mortality in patients with various heart diseases. However, the evidence is still scarce in patients with SIHD, especially those without revascularization. The Pre-START study, a multicenter prospective single-arm open-label pilot study, will evaluate the efficacy and safety of CR on HRQL, exercise capacity, and clinical outcomes. We acknowledge that our sample size is too small and the observation period is too short to evaluate clinical outcomes. However, this study will provide valuable evidence to elucidate the efficacy and safety of CR in patients with SIHD and indispensable information for a subsequent RCT.

Sources of Funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant no. JP19K10509).

Disclosures

All authors have reported that they have no relationships relevant to the contents of this article to disclose. S.K. is a member of Circulation Reports’ Editorial Team.

IRB Information

This study was approved by the Ethics Committee of the Kyoto Prefectural University of Medicine (ERB-C-2235).

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