Exercise intensity in patients with cardiovascular diseases : systematic review with meta-analysis

International Journal of Environmental Research and Public Health Systematic Review Exercise Intensity in Patients with Cardiovascular Diseases: Systematic Review with Meta-Analysis Catarina Gonçalves 1,2 , Armando Raimundo 1,2 , Ana Abreu 3and Jorge Bravo 1,2,*   Citation: Gonçalves, C.; Raimundo, A.; Abreu, A.; Bravo, J. Exercise Intensity in Patients with Cardiovascular Diseases: Systematic Review with Meta-Analysis. Int. J. Environ. Res. Public Health 2021,18, 3574. https://doi.org/10.3390/ ijerph18073574 Academic Editor: Paul B. Tchounwou Received: 23 February 2021 Accepted: 25 March 2021 Published: 30 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1Departamento de Desporto e Saúde, Escola de Saúde e Desenvolvimento Humano, Universidade de Évora, Largo dos Colegiais, 7000 Évora, Portugal; [email protected] (C.G.); [email protected] (A.R.) 2Comprehensive Health Research Centre (CHRC), Universidade de Évora, Largo dos Colegiais, 7000 Évora, Portugal 3Servico de Cardiologia, Hospital Universitário de Santa Maria/Centro Hospitalar Universitário Lisboa Norte (CHULN), Centro Académico de Medicina de Lisboa (CAML), Centro Cardiovascular da Universidade de Lisboa (CCUL), Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal; [email protected] *Correspondence: jor[email protected] Abstract: Exercise-induced improvements in the VO 2 peak of cardiac rehabilitation participants are well documented. However, optimal exercise intensity remains doubtful. This study aimed to identify the optimal exercise intensity and program length to improve VO 2 peak in patients with cardiovascular diseases (CVDs) following cardiac rehabilitation. Randomized controlled trials (RCTs) included a control group and at least one exercise group. RCTs assessed cardiorespiratory fitness (CRF) changes resulting from exercise interventions and reported exercise intensity, risk ratio, and confidence intervals (CIs). The primary outcome was CRF (VO 2 peak or VO 2 at anaerobic threshold). Two hundred and twenty-one studies were found from the initial search (CENTRAL, MEDLINE, CINAHL and SPORTDiscus). Following inclusion criteria, 16 RCTs were considered. Meta-regression analyses revealed that VO 2 peak significantly increased in all intensity categories. Moderate-intensity interventions were associated with a moderate increase in relative VO 2 peak (SMD = 0.71 mL-kg −1 -min −1 ; 95% CI = [0.27–1.15]; p= 0.001) with moderate heterogeneity (I 2 = 45%). Moderate-to-vigorous-intensity and vigorous-intensity interventions were associated with a large increase in relative VO 2 peak (SMD = 1.84 mL-kg −1 -min −1 ; 95% CI = [1.18–2.50], p< 0.001 and SMD = 1.80 mL-kg −1 -min −1 ; 95% CI = [0.82–2.78] p= 0.001, respectively), and were also highly heterogeneous with I 2 values of 91% and 95% (p< 0.001), respectively. Moderate-to-vigorous and vigorous-intensity interventions, conducted for 6–12 weeks, were more effective at improving CVD patients’ CRF. Keywords: cardiac rehabilitation; cardiorespiratory fitness; exercise therapy; heart diseases; high-intensity intermittent exercise 1. Introduction Cardiovascular diseases (CVDs) are the leading cause of mortality in today’s society, being responsible for up to one-third of all deaths worldwide and 50% of all deaths in Europe, and this scenario is expected to worsen in the coming years [1]. The concept of cardiac rehabilitation (CR) has been defined as the effort towards cardiovascular risk factor reduction, designed to lessen the chance of a subsequent cardiac event, and to slow and perhaps stop the progression of the disease process. In the context of CR programs, exercise training has been recognized as one of the main components, combined with education, control, pharmacological adherence and lifestyle changes of cardiovascular risk factors [ 2 ]. Physical exercise inclusion in CR programs resulted in several beneficial effects on cardiovascular functional capacity, quality of life, risk factor modification, psychological profile, hospital readmissions, and mortality [ 3 , 4 ]. Such benefits can be justified by a 20% reduction in mortality from all causes and in the levels of Int. J. Environ. Res. Public Health 2021,18, 3574. https://doi.org/10.3390/ijerph18073574 https://www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2021,18, 3574 2 of 19 cardiorespiratory fitness (CRF) for each metabolic equivalent improvement (MET) in CRF of patients with CVD [5]. Exercise programs for patients with CVD traditionally involve mostly lowto moderateintensity continuous aerobic exercise training, with the consensus that one of the benefits of aerobic exercise is the increase in peak oxygen uptake (VO 2 peak) [ 6 – 8 ]. Continuous aerobic exercise training implicates higher durations under moderate-intensity and nonvariable aerobic activity (60–80% of VO 2 peak) [ 9 – 12 ], compared to high-intensity protocols, which consist of intermittent, short high-intensity work periods (85–100% of VO 2 peak) with relative resting periods [13,14]. Exercise intensity appears to influence the number of cardioprotective benefits achieved from aerobic exercise [ 15 , 16 ]. The current consensus recommends that exercise intensity prescribed for patients with CVD should be approximately 60% of the maximal heart rate (MHR), 50% of the heart rate reserve (HRR), or 12–13 on the Borg scale. Intensities around 85% MHR, 80% HRR, or 15–16 on the Borg scale should represent the upper limits [ 6 ]. Additionally, high-intensity protocols (85–100% of VO 2 peak) appear to be of particular interest to scientists, considering their application in patients with CVD based on the effects on the cardiorespiratory and muscle systems [ 7 ]. High-intensity protocols elicit a greater training stimulus than moderate continuous exercise in improving maximal aerobic capacity [ 8 – 19 ]. In addition, high-intensity exercise appears to improve the limiting factors of VO 2 peak, and VO 2 peak itself has been found to be more effective in improving cardiovascular risk factors than moderate-intensity exercise [17,19]. Training sessions based on moderate-intensity continuous exercise have shown improvements in HRR after eight weeks [ 20 ] and after 12 weeks [ 21 , 22 ]. Moderateto highintensity continuous exercise (6 and 12 MET, corresponding to 21 and 42 mL-kg −1 -min −1 of VO 2 peak) has also been shown to reduce all-cause mortality in healthy individuals, independent of activity duration [ 7 ], and reduce the risk of heart disease [ 15 ], supporting the need to further investigate the potential health effects of protocols based on higher intensities. Therefore, during the last two decades, several studies have demonstrated that high-intensity exercise protocols induce more beneficial cardiovascular adaptations in patients with mild-to-severe heart disease when compared to moderate-intensity exercise protocols [8,17–19]. A recent meta-analysis [ 23 ] reported higher improvements in maximal aerobic capacity after high-intensity interval training (HIIT) programs compared to moderate-intensity programs. Nevertheless, the optimum exercise intensity prescription in patients with CVD is still a subject of debate. A recent systematic review on the topic [ 24 ] did not report optimal intensity prescription (e.g., the intensity interval that is most effective during exercise interventions to induce favorable changes in aerobic capacity). Thus, despite the literature being replete with studies showing that regular and structured exercise is beneficial for CVD patients, the optimal intensity and length of exercise interventions that bring about greater benefits remain equivocal. Hence, the objective of this systematic review with meta-analysis was to identify, through Randomized Controlled Trials (RCTs) of exercise-based CR, the most effective exercise intensity and intervention length to optimize VO2peak in patients with CVD. 2. Materials and Methods This systematic review was undertaken as detailed in the protocol registered with PROSPERO (Registration Number CRD42018097319). 2.1. Search Strategy The search strategies were designed in accordance with the methods suggested by the Cochrane Handbook for Systematic Reviews of Interventions [ 25 ]. The following databases were searched from their inception to January 2021: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), CINAHL (EBSCO) and SPORTDiscus. Data are provided as the risk difference (95% CI), based on RCTs published until January Int. J. Environ. Res. Public Health 2021,18, 3574 3 of 19 2021, ensuring that all studies have been included if reporting data on established outcomes. Reference lists of eligible studies were also systematically searched. We used the PICO model [ 26 ] to identify free text terms and controlled vocabulary terms to create our searches. The following key concepts were chosen: “Patients with cardiovascular diseases” AND “Cardiac Rehabilitation” AND “Exercise Intensity” AND “Cardiorespiratory Fitness”. The search strategy for the MEDLINE (Ovid) database is available in the Supplementary Materials of this manuscript. 2.2. Inclusion Criteria The inclusion criteria were full-length research articles published in peer-reviewed journals in the English language with no limits set on the date of first publication or gender. Only RCTs up to January 2021 were eligible. Studies included participants who were diagnosed with CVD, such as those involved in some exercise programs, assessed by analyzing expired air during a maximal cardiopulmonary exercise test at baseline and postintervention. We included RCTs to compare aerobic capacity changes resulting from exercise interventions, with an exercise group (or groups), that described exercise intensities, including data for risk ratio and CI. Studies were required to detail the exercise prescription in patients with CVD, including the frequency, intensity and duration of each session, mode of exercise and the overall length of intervention. The main authors of studies and experts in this field were asked for any missed, unreported, or ongoing trials. The quantitative synthesis included studies reporting sample size and the mean and standard deviations (SDs) for VO 2 peak preintervention and postintervention. 2.3. Exclusion Criteria Abstracts, conference presentations or posters, letters to editors or book chapters, unpublished papers, and retrospective design studies were excluded. In addition, studies were excluded if participants had documented heart failure (ejection fraction < 40%) or arrhythmia, they were targeting a specific comorbidity (e.g., diabetes, chronic obstructive pulmonary disease, or stroke) and they featured interventions involving resistance exercises only. We also excluded studies based on exercise prescriptions including testing food supplements and nutritional or pharmacological aids. Studies were also excluded if baseline or postintervention data were not published, and the authors were not available for contact or did not wish to provide the missing data. 2.4. Study Selection and Data Extraction All data were extracted by the principal investigator and their accuracy was assessed by the second author. The EndNote software (Clarivate Analytics, Philadelphia, PA, USA) was used to import, manage and remove duplicated articles for final review. After removing the duplicates, the two reviewers independently reviewed titles and abstracts against the inclusion/exclusion criteria. If in doubt, the full texts were evaluated to verify if they met the criteria. Subsequently, abstracts were selected for eligibility, and full manuscripts were retrieved for further evaluation of eligibility. Discrepancies were resolved between both authors, and a third expert, not involved in the previous procedures, was consulted to verify the ratings. The selection process was entered into a Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) diagram [27] (Figure 1). Int. J. Environ. Res. Public Health 2021,18, 3574 4 of 19 Int. J. Environ. Res. Public Health 2021, 18, x FOR PEER REVIEW 4 of 18 Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) diagram of literature search strategies. For each RCT, the author, year of publication, participant characteristics (age, gender, and primary diagnosis), description of the exercise testing protocol and description of the intervention (session frequency and duration, intervention length, exercise modality, resistance training, type of training (interval/continuous), supervision (clinic/home) and intervention type) were extracted. The preand post-VO2peak values and change in VO2peak were also extracted to assess change in CRF. Outcomes were extracted in relative (mL-kg−1-min−1) and absolute (L-min−1) terms. Outcomes reported in METs were converted to relative terms (METs × 3.5 mL-kg−1-min−1). Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) diagram of literature search strategies. For each RCT, the author, year of publication, participant characteristics (age, gender, and primary diagnosis), description of the exercise testing protocol and description of Int. J. Environ. Res. Public Health 2021,18, 3574 5 of 19 the intervention (session frequency and duration, intervention length, exercise modality, resistance training, type of training (interval/continuous), supervision (clinic/home) and intervention type) were extracted. The preand post-VO 2 peak values and change in VO 2 peak were also extracted to assess change in CRF. Outcomes were extracted in relative (mL-kg −1 -min −1 ) and absolute (L-min −1 ) terms. Outcomes reported in METs were converted to relative terms (METs ×3.5 mL-kg−1-min−1). 2.5. Assessment of Potential Bias The risk of bias was assessed using the modified Cochrane collaboration tool [ 25 ], developed in 2005 to assess and report the risk of bias in RCTs. Bias assessment results from the judgment (high, low, or unclear) of individual elements from seven sources of bias covered six domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other bias (criteria for selected patients in the studies and the country in which the study was conducted). A detailed description of each source of bias and support for judgement is available elsewhere [ 25 ]. The lead reviewer found 16 studies, and discrepancies were discussed and resolved. 2.6. Data Treatment and Analysis The systematic review was stratified by intensities based on proposed cut-offs [ 28 ]. Thereby, each exercise program was ranked as light-, moderateor vigorous-intensity aerobic exercise (Table 1). Table 1. Classification of exercise intensity based on physiological and perceived exertion responses. %VO2max %HRpeak %HRreserve/ %VO2reserve Perceived Exertion * Light 37–45 57–63 30–39 RPE 9–11 Moderate 46–63 64–76 40–59 RPE 12–13 Vigorous 64–90 77–95 60–89 RPE 14–17 Near maximal to maximal ≥91 ≥95 ≥90 RPE ≥18 Table adapted from American College of Sports Medicine (ACSM) [ 28 ] and Mitchell et al. [ 23 ]. * As per the Borg 6–20 RPE scale. %VO 2 max, percentage of maximal oxygen uptake; %HRpeak, percentage of peak heart rate; %HRreserve, percentage of heart rate reserve; %VO 2 reserve, percentage of oxygen uptake reserve; RPE, rating of perceived exertion. Studies reporting an intensity that covers the categories of moderate intensity and vigorous intensity (e.g., 60–70% of VO 2 peak) were classified as “moderate-to-vigorous” intensity [ 28 ]. A separate meta-analysis was performed for each intensity category and length of the trial—e.g., “short-term” (0–6 weeks), “medium-term” (7–12 weeks), and “long-term” (>12 weeks). The following subgroup analysis was conducted to explore significant heterogeneity: participant characteristics, including (1) age, (2) gender and (3) primary diagnosis; description of the exercise testing protocol and description of the intervention, including (4) session frequency and (5) duration, (6) intervention length, (7) exercise modality, (8) resistance training, (9) type of training (interval/continuous), (10) supervision (clinic/home), (11) intervention type (exercise only/comprehensive); and (12) preand postpeak VO 2 values or change in VO2peak. Heterogeneity amongst the included studies was first explored qualitatively by comparing the characteristics of the included trials and then by visually inspecting forest plots. It was also assessed quantitatively by the Chi 2 and I 2 statistics. Heterogeneity was considered minimal if I 2 fell between 0–30%, moderate if 30–50%, substantial if 50–90%, and considerable if >90% [25]. I2and Chi2were considered significant at p< 0.1. Int. J. Environ. Res. Public Health 2021,18, 3574 6 of 19 Due to the heterogeneity of the protocol, mean differences (MDs) were used, dividing the mean values between different intensities. The differences in means were grouped using the random-effects model. A random-effects model and a standardized means model of averages were used to explain the differences in the methodology of the studies included both in the intensities and length of intervention to ensure a conservative estimate was calculated. A sensitivity analysis was conducted to investigate the possible effects of specific studies on heterogeneity and overall effect. The dichotomous and continuous variables of the studies were compared with the extracted potential VO 2 peak moderator factors. The effect of treatment was calculated for each study for the change in VO 2 peak over the intervention using the pooled betweensubject SD at both time points. Effects were quantified as trivial (<0.20), small (0.21–0.60), moderate (0.61–1.20), large (1.21–2.00) and very large (>2.00) [ 29 ], with the precision of effect size estimates assessed using 95% CI. Pooled SMD was back-transformed using the pooled between-subject SD at baseline within each intensity category. If SD for the mean change in VO 2 peak across the intervention was not published [ 30 ], it was used for p-value entry. If no p-values or standard deviations were published, the standard error (SE) of the MD was inputted based on the correlation between preintervention and postintervention outcomes [ 31 ]. The imputed SE was then used to calculate the 95% CI for the standardized effect of each study. For outcomes expressed as change in relative VO 2 peak (mL-kg −1 -min −1 ), a correlation of r = 0.54 from a similar meta-analysis [ 32 ] was used. A sensitivity analysis was performed using the estimated correlations of r = 0.30 and 0.70. Publication bias was analyzed using a funnel plot derived in RevMan5.3 software [ 30 ]. The publication bias for the different conditions analyzed (prevs. postintervention) was assessed by examining the asymmetry of a funnel plot using Egger’s test, and p ≤ 0.05 was considered to be statistically significant. 3. Results The initial search resulted in 221 studies. All data were extracted by the principal investigator and their accuracy was assessed by a second author. Search results were entered into EndNote software (Clarivate Analytics, Philadelphia, PA, USA), a reference management tool, and duplicates were removed. After the duplicates were removed, the titles of 212 studies were reviewed. Following a screening of potential records, 49 articles were reviewed for eligibility and their reference lists screened. Twenty-two RCTs met eligibility criteria for the systematic review and meta-analysis. According to our inclusion criteria, sixteen studies [9–14,20–22,33–39] were included in this systematic review (Figure 1). The main characteristics of the studies and training interventions are described in Tables 2and 3, respectively. Table 2. Subgroup analyses assessing potential moderating factors for VO 2 peak increase in studies included in the meta-analysis by population characteristics. Research Studies Peak VO2 Group N References MD (95% CI) I2pap-Difference b No. of participants <20 4 Ghroubi et al. [20], Tamburus et al. [14], Wu et al. [33], Chuang et al. [34]2.62 (1.65, 3.58) 88 <0.001 0.78 ≥20 12 Abolahrari-Shirazi et al. [9], Blumenthal et al. [21], Giallauria et al. [10–12,36], Kitzman et al. [22], Kraal et al. [36], Kubo et al. [38], Legramante et al. [37], Villelabeitia et al. [13], Zheng et al. [35] 2.75 (2.58, 2.93) 97 <0.001 Int. J. Environ. Res. Public Health 2021,18, 3574 7 of 19 Table 2. Cont. Research Studies Peak VO2 Group N References MD (95% CI) I2pap-Difference b Age, years <60 9 Abolahrari-Shirazi et al. [9], Ghroubi et al. [20], Giallauria et al. [10,12,36], Kraal et al. [39], Kubo et al. [38], Tamburus et al. [14], Villelabeitia et al. [13] 4.40 (0.79, 8.01) 97 0.02 0.75 ≥60 6 Blumenthal et al. [21], Chuang et al. [34], Giallauria et al. [11], Kitzman et al. [22], Legramante et al. [37], Wu et al. [33] 3.48 (2.09, 4.87) 79 <0.001 Not reported 1 Zheng et al. [35] 3.10 (2.06, 4.14) 0 <0.001 Diagnosis CAD only 3 Blumenthal et al. [21], Tamburus et al. [14], Villelabeitia et al. [13]6.41 (−2.70, 15.53) 99 0.17 0.03 CABG only 4Chuang et al. [34], Ghroubi et al. [20], Legramante et al. [37], Wu et al. [33]4.27 (1.60, 6.94) 85 0.002 PCI only 1 Abolahrari-Shirazi et al. [9] 8.20 (4.68, 11.72) 0 <0.001 CABG/PCI 1 Kraal et al. [39] 3.20 (0.36, 6.04) 0 0.03 MI 6 Giallauria et al. [10–12,36], Kubo et al. [38], Zheng et al. [35]2.65 (0.56, 4.74) 91 0.01 FMD 1 Kitzman et al. [22] 1.60 (−0.13, 3.33) 0 0.07 Study location America 2 Kitzman et al. [22], Tamburus et al. [14]1.38 (0.39, 2.36) 0 0.006 0.01 Africa 1 Ghroubi et al. [20] 1.70 (−1.07, 4.47) 0 0.23 Asia 5 Abolahrari-Shirazi et al. [9], Chuang et al. [34], Kubo et al. [38], Wu et al. [33], Zheng et al. [35] 5.33 (2.90, 7.76) 80 <0.001 Europe 8 Blumenthal et al. [21], Giallauria et al. [10–12,36], Kraal et al. [39], Legramante et al. [37], Villelabeitia et al. [13] 4.23 (1.50, 6.95) 98 0.002 95% CI, 95% confidence interval. I2, heterogeneity. MD, mean difference. Peak VO2, peak oxygen uptake. Conditions: MI, myocardial infarction. CABG, coronary artery bypass graft. PCI, percutaneous coronary intervention. CAD, coronary artery disease. FMD, endothelialdependent flow-mediated arterial dilation. Certain enrolled studies were not included because the value used for subgroup analysis was not reported in them. a Test for overall effect. b Test for subgroup differences. Int. J. Environ. Res. Public Health 2021,18, 3574 8 of 19 Table 3. Subgroup analyses assessing potential moderating factors for VO 2 peak increase in studies included in the meta-analysis by population characteristics. Research Studies Peak VO2 Group N References MD (95% CI) I2pap-Difference b Length, weeks <6 1 Legramante et al. [37] 2.60 (2.41, 2.79) 0 <0.001 0.42 6–12 9 Abolahrari-Shirazi et al. [9], Chuang et al. [34], Ghroubi et al. [20], Giallauria et al. [ 10 , 36 ], Kraal et al. [ 39 ], Kubo et al. [38], Villelabeitia et al. [13], Wu et al. [33] 5.31 (1.24, 9.38) 97 0.01 >12 6 Blumenthal et al. [21], Giallauria et al. [11,12], Kitzman et al. [22], Tamburus et al. [14], Zheng et al. [35] 2.50 (1.60, 3.41) 52 <0.001 Frequency, sessions/week 1–2 2 Chuang et al. [34], Kraal et al. [39] 3.98 (1.96, 6.01) 0 0.001 0.17 3–4 13 Abolahrari-Shirazi et al. [9], Blumenthal et al. [21], Ghroubi et al. [20], Giallauria et al. [10–12,36], Kitzman et al. [22], Kubo et al. [38], Tamburus et al. [14], Villelabeitia et al. [13], Wu et al. [33], Zheng et al. [35] 4.21 (1.82, 6.60) 96 0.006 5–7 1 Legramante et al. [37] 2.60 (2.41, 2.79) 0 <0.001 Supervision Clinic 12 Blumenthal et al. [21], Chuang et al. [ 34 ], Ghroubi et al. [ 20 ], Giallauria et al. [10–12], Kitzman et al. [22], Kubo et al. [38], Legramante et al. [37], Tamburus et al. [14], Villelabeitia et al. [13], Zheng et al. [35] 4.01 (2.30, 5.72) 96 <0.001 0.02 Home 1 Wu et al. [33] 8.50 (5.78, 11.22) 0 <0.001 Mixed 3 Abolahrari-Shirazi et al. [9], Giallauria et al. [36], Kraal et al. [39]2.99 (−2.89, 8.87) 94 0.32 Intervention type Continuous 13 Abolahrari-Shirazi et al. [9], Blumenthal et al. [21], Chuang et al. [34], Giallauria et al. [11,12,36], Kitzman et al. [22], Kraal et al. [39], Kubo et al. [38], Legramante et al. [37], Wu et al. [33], Zheng et al. [35] 3.27 (2.23, 4.32) 87 <0.001 0.44 Interval 2 Tamburus et al. [14], Villelabeitia et al. [13]8.67 (−5.86, 23.21) 99 0.24 Mixed 1 Ghroubi et al. [20] 1.70 (−1.07, 4.47) 0 0.23 Int. J. Environ. Res. Public Health 2021,18, 3574 9 of 19 Table 3. Cont. Research Studies Peak VO2 Group N References MD (95% CI) I2pap-Difference b Mode Cycle ergometer 7 Ghroubi et al. [20], Giallauria et al. [10–12], Tamburus et al. [14], Villelabeitia et al. [ 13 ], Zheng et al. [ 35 ] 4.90 [1.52, 8.27) 97 0.005 0.23 Treadmill 1 Chuang et al. [34] 4.80 (1.91, 7.69) 0 0.001 Walking 1 Blumenthal et al. [21] 1.90 (0.20, 3.60) 0 0.03 Mixed (treadmill, walking, cycling, calisthenics or/and arm/leg ergometer) 7 Abolahrari-Shirazi et al. [9], Giallauria et al. [36], Kitzman et al. [22], Kraal et al. [39], Kubo et al. [37], Legramante et al. [37], Wu et al. [33] 3.28 (1.17, 5.39) 92 0.002 Exercise type Aerobic 13 Blumenthal et al. [21], Chuang et al. [ 34 ], Ghroubi et al. [ 20 ], Giallauria et al. [10,12,36], Kitzman et al. [22], Kraal et al. [39], Kubo et al. [38], Tamburus et al. [14], Villelabeitia et al. [13], Wu et al. [33], Zheng et al. [35] 3.94 (1.55, 6.34) 96 0.001 0.86 Aerobic and Resistance 3Abolahrari-Shirazi et al. [9], Giallauria et al. [11], Legramante et al. [37]4.24 (1.82, 6.67) 81 0.001 Intensity Moderate 3 Giallauria et al. [10], Kubo et al. [38], Villelabeitia et al. [13]2.90 (1.64, 4.16) 0 <0.001 0.03 Moderate-tovigorous 10 Abolahrari-Shirazi et al. [9], Chuang et al. [34], Giallauria et al. [11,12,36], Kitzman et al. [ 22 ], Kraal et al. [ 39 ], Wu et al. [33], Zheng et al. [35] 5.07 (3.43, 6.72) 92 <0.001 Vigorous 3 Blumenthal et al. [21], Ghroubi et al. [20], Giallauria et al. [10], Legramante et al. [37], Tamburus et al. [14], Villelabeitia et al. [13] 2.43 (1.33, 3.54) 75 <0.001 95% CI, 95% confidence interval. I 2 , heterogeneity. MD, mean difference. Peak VO2, peak oxygen uptake. Certain enrolled studies were not included because the value used for subgroup analysis was not reported in them. a Test for overall effect. b Test for subgroup differences. 3.1. Risk of Bias Sixteen studies were scored by two reviewers, and an absolute agreement (r = 0.94) was obtained from the intraclass correlation coefficient (ICC). Bias was assessed as a judgment (high, low, or unclear) for individual elements from seven sources of bias and the following ICCs for absolute agreement between the two reviewers were obtained: random sequence generation for selection bias (r = 0.90), allocation concealment for selection bias (r = 0.92), blinding of participants and personnel for performance bias (r = 0.98), blinding of outcome assessment for detection bias (r = 0.94), incomplete outcome data for attrition bias (r = 0.79), selective reporting for reporting bias (r = 0.98) and inclusion criteria of patients in the studies and the country in which the study was conducted for other bias (r = 0.88). The risk of bias in the 16 included trials is summarized in Figure 2. Int. J. Environ. Res. Public Health 2021,18, 3574 16 of 19 Future studies would benefit from being between 6 and 12 weeks in length with an intervention activity carried out at least three times weekly, ensuring that the correct intensity is maintained. For example, appropriate goals for vigorous-intensity exercise include ≥ 85% VO 2 peak or ≥ 85% HRR or ≥ 90% HRM and, for moderate intensity, 50–75% VO 2 peak or 50–75% HRR or 50–80% HRM. In addition, large ranges of exercise intensities should not be prescribed based on HR responses to exercise. This would allow a more accurate calculation of the exact effects of intensities on CRF and to determine the ideal and most effective “dose” for people with heart problems. Future research should include methods to appropriately describe the compliance of participants with the prescribed exercise intensity and attendance of exercise sessions. Studies should report standard deviations, conceal allocation, and blind assessors to improve study quality. Moreover, future studies should aim to recruit more women and older participants (<76 years) to ensure vigorous-intensity interventions are more effective than moderate-intensity ones in improving CRF for a broader range of patients with CVD. Finally, further studies that investigate the longer-term benefits of vigorous-intensity interventions and whether these adaptations are maintained would also be beneficial. 5. Conclusions The most effective doses of exercise intensity to optimize CRF were moderate-tovigorous and vigorous exercise. Interventions to enhance CRF in patients with CVD are most effective if conducted for 6 to 12 weeks. More research is needed to understand within the moderate-to-vigorous-intensity category which percentage results in increased CRF, assisting in the design of specific prescription protocols. This review may suggest that countries without guidelines for patients with CVD regarding the intensity of exercise programs, as well as countries with guidelines that recommend lower intensity exercise, should include moderate-to-vigorous intensity and vigorous intensity. What is already known:  Cardiovascular diseases are the leading causes of mortality in today’s society. They are responsible for up to 30% of all deaths worldwide and 48% of deaths in Europe, and it is expected that these figures will increase in the coming years.  Exercise programs in patients with cardiovascular disease have several beneficial effects on cardiovascular functional capacity, quality of life, risk factors modification, psychological profile, hospital readmissions, and mortality.  Exercise-based interventions seem to significantly improve cardiorespiratory fitness in patients following a cardiac event or surgery, but little is known regarding the differential effects of prescribed exercise intensity. What are the new findings?  Exercise interventions for patients with cardiovascular disease tend include large ranges of exercise intensities based on heart rate responses to exercise.  The most effective doses of exercise intensity to optimize cardiorespiratory fitness were moderate-to-vigorous and vigorous-intensity exercises, being more effective when conducted for 6 to 12 weeks.  More research is needed to understand within the moderate-to-vigorousand vigorousintensity categories the percentage that specifically helps to increase cardiorespiratory fitness and the ability to establish specific prescription protocols. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/ijerph18073574/s1, Table S1: Complete search strategy for MEDLINE, searched from inception until January 2021; Figure S2: Summary of study characteristics; Figure S3: Outcome of the risk of bias assessment; Figure S4: List of references for included studies. Author Contributions: Conceptualization, C.G., J.B., A.A. and A.R.; methodology, C.G. and J.B.; software, C.G.; validation, C.G. and J.B.; formal analysis, C.G. and J.B.; investigation, C.G. and Int. J. Environ. Res. Public Health 2021,18, 3574 17 of 19 J.B.; resources, C.G. and J.B.; data curation, C.G. and J.B.; writing—original draft preparation, C.G.; writing—review and editing, C.G., J.B., A.A. and A.R.; visualization, C.G., J.B., A.A. and A.R.; supervision, C.G., J.B. and A.R.; project administration, C.G., J.B. and A.R.; funding acquisition, C.G., A.A. and A.R. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Fundação para a Ciência e Tecnologia (Portugal), grant number SFRH/BD/138326/2018. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. 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