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Original Investigation |

Global Secondary Prevention Strategies to Limit Event Recurrence After Myocardial Infarction:  Results of the GOSPEL Study, a Multicenter, Randomized Controlled Trial From the Italian Cardiac Rehabilitation Network FREE

Pantaleo Giannuzzi, MD; Pier Luigi Temporelli, MD; Roberto Marchioli, MD; Aldo Pietro Maggioni, MD; Gianluigi Balestroni, PhD; Vincenzo Ceci, MD; Carmine Chieffo, MD; Marinella Gattone, MD; Raffaele Griffo, MD; Carlo Schweiger, MD; Luigi Tavazzi, MD; Stefano Urbinati, MD; Franco Valagussa, MD; Diego Vanuzzo, MD; GOSPEL Investigators
[+] Author Affiliations

Died December 1, 2006.


Arch Intern Med. 2008;168(20):2194-2204. doi:10.1001/archinte.168.20.2194.
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Published online

Background  Secondary prevention is not adequately implemented after myocardial infarction (MI). We assessed the effect on quality of care and prognosis of a long-term, relatively intensive rehabilitation strategy after MI.

Methods  We conducted a multicenter, randomized controlled trial in patients following standard post-MI cardiac rehabilitation, comparing a long-term, reinforced, multifactorial educational and behavioral intervention with usual care. A total of 3241 patients with recent MI were randomized to a 3-year multifactorial continued educational and behavioral program (intervention group; n = 1620) or usual care (control group; n = 1621). The combination of cardiovascular (CV) mortality, nonfatal MI, nonfatal stroke, and hospitalization for angina pectoris, heart failure, or urgent revascularization procedure was the primary end point. Other end points were major CV events, major cardiac and cerebrovascular events, lifestyle habits, and drug prescriptions.

Results  End point events occurred in 556 patients (17.2%). Compared with usual care, the intensive intervention did not decrease the primary end point significantly (16.1% vs 18.2%; hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.74-1.04). However, the intensive intervention decreased several secondary end points: CV mortality plus nonfatal MI and stroke (3.2% vs 4.8%; HR, 0.67; 95% CI, 0.47-0.95), cardiac death plus nonfatal myocardial infarction (2.5% vs 4.0%; HR, 0.64; 95% CI, 0.43-0.94), and nonfatal MI (1.4% vs 2.7%; HR, 0.52; 95% CI, 0.31-0.86). A marked improvement in lifestyle habits (ie, exercise, diet, psychosocial stress, less deterioration of body weight control) and in prescription of drugs for secondary prevention was seen in the intervention group.

Conclusion  The GOSPEL Study is the first trial to our knowledge to demonstrate that a multifactorial, continued reinforced intervention up to 3 years after rehabilitation following MI is effective in decreasing the risk of several important CV outcomes, particularly nonfatal MI, although the overall effect is small.

Trial Registration  ClinicalTrials.gov Identifier: NCT00421876

Figures in this Article

Cardiac rehabilitation programs (CRPs) after a diagnosis of coronary heart disease (CHD) have gradually evolved over the past 2 decades from an exercise-based intervention into a comprehensive, professional lifestyle program including smoking cessation, diet modification, control of cardiovascular (CV) risk factors, and behavioral interventions aimed at changing exercise, psychological stress, and vocational components of lifestyle habits.16 Current CRP procedures rely on short-term interventions and are not adequately implemented because patients with CHD do not reach the therapeutic goals for their specific risk profile.710 Short-term approaches are, in fact, unlikely to yield long-term benefits, to have an impact on quality of life, or to decrease morbidity and mortality.1014 Finally, discontinuation of medication after myocardial infarction (MI) is frequent and occurs early after hospital discharge, although the issue of undertreatment has been addressed by only a few, small-scale studies.11,13,15,16

The Global Secondary Prevention Strategies to Limit Event Recurrence After Myocardial Infarction (GOSPEL) Study is a randomized controlled clinical trial designed to assess the efficacy of 2 strategies of secondary prevention with different duration and intensity of intervention following post-MI standard CRP.

The protocol of the GOSPEL Study has been published elsewhere.17 In brief, the GOSPEL Study was a randomized trial performed in 78 Italian cardiac rehabilitation centers adopting a prospective, randomized, open-label, blinded, end point evaluation design and testing the efficacy of long-term, reinforced, multifactorial educational and behavioral intervention vs usual care after MI.

The institutional review boards of participating centers approved the protocol, and all patients provided written informed consent. Centers were selected for the study on the basis of documented experience in CRP, availability of expert personnel trained in counseling techniques, and a tradition of research in CV disease. The investigators underwent adequate training in the study procedures before the start of the trial. The study was independently managed and analyzed by the coordinating center.

To increase the generalizability of the results, broad eligibility criteria were adopted. Patients enrolled in the GOSPEL Study who had had a recent MI (within <3 months) were routinely referred to a cardiac rehabilitation center, residential or ambulatory, irrespective of revascularization procedures received after the index event. Exclusion criteria were age older than 75 years, an unfavorable short-term outlook (eg, overt congestive heart failure, cancer), any systemic disease limiting exercise, and inability to participate in the trial for any logistic reason.

All patients completed a standard CRP lasting approximately 1 month and consisting of supervised exercise sessions and comprehensive lifestyle and risk factor management along with optimization of medical therapy. After completion of the standard CRP, the patients were randomized in a one-to-one fashion to either an intensive, 3-year-long, multifactorial intervention (intervention group) or usual care (control group). Randomization was centrally determined by fax at the coordinating secretariat using a computerized algorithm.

We planned the procedures of the trial to resemble as closely as possible the routine care after MI. Patients were required to perform follow-up visits at 6 months, 1 year, 2 years, 3 years, and then yearly until December 2005, when the last randomized patients completed the planned 3-year program (Figure 1).

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Figure 1.

Study flowchart.

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EXPERIMENTAL INTERVENTION

The multifactorial, continued educational, and behavioral program was performed by a cardiac rehabilitation team composed of a specialist cardiac nurse, a physiotherapist, and a cardiologist (who was the supervisor). A clinical psychologist and occupational therapist could be recruited if needed.

A letter was sent to patients' family physicians informing them of the study and inviting their collaboration in the study objectives. Comprehensive cardiac rehabilitation sessions with one-to-one support were held monthly from month 1 to month 6, then every 6 months for 3 years. Each session consisted of 30 minutes of supervised aerobic exercise, plus lifestyle and risk factor counseling lasting at least 1 hour and reinforcement of preventive interventions lasting approximately 30 minutes. To improve adherence to lifestyle modification and help patients adopt a positive role in the care of their own health, a booklet explaining how to deal with exercise, diet, smoking cessation, and stress management was distributed. The mutual support of family members (eg, spouses) was encouraged in ad hoc meetings together with the patients to make correct lifestyle habits more likely to be maintained in the long run.18

The intervention was aimed at individualizing risk factor and lifestyle management, and pharmacological treatments were based on current guidelines.3,5 The targets of the intervention strategy were to give up smoking, adopt a healthy Mediterranean diet,19 increase physical activity up to at least 3 h/wk at 60% to 75% of the mean maximum heart rate, maintain body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 25 or less, blood pressure of 140/85 mm Hg or lower (≤130/80 mm Hg for patients with diabetes mellitus [DM]), total cholesterol level of 200 mg/dL or lower, low-density lipoprotein (LDL) cholesterol level lower than 100 mg/dL, blood glucose level of 110 mg/dL or lower, and hemoglobin A1c (HbA1c) level lower than 7.0% in subjects with DM.35,20,21 Pharmacological treatments, including antiplatelet agents, angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARBs), β-blockers, statins, and omega-3 polyunsaturated fatty acids, were positively recommended to all patients. (To convert total cholesterol and LDL cholesterol to millimoles per liter, multiply by 0.0259; to convert HbA1c to a proportion of total hemoglobin, multiply by 0.01.)

CONTROL GROUP

A letter was sent to family physicians recommending secondary prevention goals. After the standard, post-MI CRP, patients in the usual care group reported to their reference center only to undergo the 6-month and then annual scheduled assessments. After each assessment, a copy of the results of laboratory and exercise tests was forwarded to the family physician who was responsible for any further medical decisions.

ASSESSMENTS AND PROCEDURES

Data collection procedures were the same for both groups. At baseline and at each follow-up visit, the following information was collected: vital signs and symptoms, BMI, 12-lead electrocardiogram, symptom-limited exercise stress test, check of compliance, and assessment of adverse events. Blood pressure was the mean of 2 measures taken 2 minutes apart with a manual sphygmomanometer. Laboratory analysis included fasting total cholesterol, high-density lipoprotein (HDL) and LDL cholesterol, triglyceride, fasting glucose, and HbAlc levels. An echocardiographic assessment of the left ventricular ejection fraction was performed at baseline.

Because the GOSPEL Study was designed as a large-scale, pragmatic trial with patients enrolled and followed by their own cardiologists in the real-world setting, it was deemed unlikely that full-scale questionnaires on food frequency and leisure time physical activity could be effectively administered in a busy clinical setting at multiple time points during 3 years of follow-up. Thus, a brief questionnaire was designed with food items selected to maximize detection of dietary variation among Italian adults.22,23 Questions focused on the frequency of usual consumption of cooked vegetables, raw vegetables, fruits, fish, olive oil, and butter. Each item was scored on an ordinal scale from 1 to 4 based on frequency of consumption, and scores were summed to obtain a Mediterranean diet score (score range, 6 [worst] to 24 [best]) that was evaluated in prespecified indicator categories. Questionnaires on smoking habits, leisure time physical activity (3 items; score range, 3 [most unfit] to 12 [≥ 3h/wk of exercise]), and self/stress management (7 items; score range, 28 [inadequate self/stress management] to 7 [optimal self/stress management]) were administered at each visit by a trained nurse. A psychological and quality-of-life evaluation was performed using the Cognitive Behavioral Assessment Hospital form validated for the Italian population at baseline and after 1 year.24 Information on the utilization of health care resources was collected from medical records at each study visit.

The primary combined end point included CV mortality, nonfatal MI, nonfatal stroke, hospitalization for angina pectoris or heart failure, and urgent unplanned revascularization procedure. Acute MI was defined as at least 2 of the following: chest pain of typical intensity and duration; ST-segment elevation or depression of 1 mm or more in any limb lead of the electrocardiogram, of 2 mm or more in any precordial lead, or both; or at least a doubling of necrosis enzymes. Diagnosis of nonfatal stroke required unequivocal signs or symptoms of persistent neurological deficit, with sudden onset and a duration of more than 24 hours. Diagnosis of fatal stroke was based on the same criteria. Alternatively, we used the diagnosis documented in hospital records or on death certificates. Validation of the clinical events included in the primary end points was assured by the executive committee of the study blinded to the patient's group allocation. Secondary clinical end points were major CV events (ie, CV mortality plus nonfatal MI and nonfatal stroke), cardiac events (cardiac death plus nonfatal MI), and fatal plus nonfatal stroke. Additional analyses were performed for total mortality and sudden death. Secondary end points also included the modification of diet; physical activity; smoking habits; self/stress management; total blood cholesterol, LDL and HDL cholesterol, and triglyceride levels; glycemic control; BMI; and blood pressure. In addition to measuring the effect of the interventions on lifestyle habits, the latter variables were also used to measure the feasibility of the tested strategies (eg, adherence to or compliance with them).

STATISTICAL ANALYSIS

We estimated the cumulative rate of the primary end point in the control group to be 30% over 3 years of follow-up by summing the incidence rates of the individual events included in the primary end point and discounting the final estimate to allow for multiple events in the same subject.25,26 To detect a 15% risk reduction with the intensive approach vs usual care approach with 80% power and a 2-sided significance at the α = .05 level, at least 1600 patients in each arm had to be enrolled in the study. The analysis of secondary end points was planned as part of the protocol. Owing to the limited power of such analysis, no correction for multiplicity of comparisons was envisaged for the secondary end points. Statistical analysis was intention-to-treat, using Kaplan-Meier survival curves and log-rank tests. Hazards ratios (HRs) and 95% confidence intervals (CIs) were calculated by fitting Cox proportional hazards models. Continuous data are reported as means (SDs), categorical data as percentages. Mixed models for repeated measurements with treatment as fixed effect and time as random effect were used to test the change from baseline and any time during the course of the study.2729 The difference of continuous variables between intervention and control groups during and at the end of the study was adjusted for the values at baseline.

The significance level for all tests was set at  = .05. All P values are 2-sided. All statistical analyses were performed using SAS statistical software (version 9.1; SAS Inc, Cary, North Carolina).

From January 2001 through December 2002, 3241 of 3778 eligible patients were randomized into the trial (Figure 1) and followed for 10 249.9 person-years. Vital status at the study end was ascertained for 3087 patients (95.2%). A total of 154 patients (4.7%) were lost to follow-up, and 155 (4.8%) withdrew their consent during the course of the study. These patients were followed by the GOSPEL investigators according to the procedures established in the protocol for a total of 116.6 and 170.8 person-years, respectively.

The median time from the index MI to randomization was 61 days. Baseline demographic and clinical characteristics were balanced across the 2 groups (Table 1) and define a relatively low-risk post-MI population, with 8.4% of patients older than 70 years and 7.3% with an echocardiogram-documented ejection fraction of less than 40%. Most of the patients were prescribed aspirin (84%), β-blockers (76%), statins (70%), or ACE inhibitors and ARBs (61%). Coronary revascularization procedures before randomization were performed in 67% of patients (Table 1).

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Patients Who Were Randomly Assigneda

A total of 119 patients (3.7%) withdrew from the program within the first 6 months of the study, 62 in the intervention group and 57 in the usual care group. At baseline, the characteristics of the patients who discontinued the program were comparable with those of patients who completed the final assessment visit (data not shown).

CLINICAL END POINTS

Figure 2 and Table 2 show the full efficacy profile of the interventions. The intensive intervention decreased nonsignificantly the absolute risk of the combined primary end point by 2.1% (HR, 0.88; 95% CI, 0.74-1.04; P = .12) compared with usual care. The intensive intervention decreased CV mortality plus nonfatal MI and stroke by 33% (95% CI, 0.47-0.95; P = .02), cardiac death plus nonfatal MI by 36% (95% CI, 0.43-0.94; P = .02), and nonfatal MI by 48% (95% CI, 0.31-0.86; P = .01) with respect to usual care. Total mortality, sudden death, and total stroke decreased, although not significantly, by 21% ( = .29), 38% ( = .24), and 32% ( = .33), respectively.

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Figure 2.

Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period among 3241 patients with recent myocardial infarction (MI). A, Data for the primary composite end point (cardiovascular mortality, nonfatal MI, nonfatal stroke, and hospitalization for angina pectoris, heart failure, or urgent revascularization procedure). The hazard ratio (HR) for the intensive intervention, compared with usual care, for the primary efficacy end point at the study end was 0.88 (95% confidence interval [CI], 0.74-1.04; P = .12). B, Data for the secondary efficacy end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke). The HR for the intensive intervention, compared with usual care, for the primary efficacy end point at the study end was 0.67 (95% CI, 0.47-0.95; P = .02). C, Data for the secondary efficacy end point (cardiac death plus nonfatal MI). The HR for the intensive intervention, compared with usual care, for the primary efficacy end point at the study end was 0.64 (95% CI, 0.43-0.94; P = .02). D, Data for the secondary efficacy end point (fatal plus nonfatal stroke). The HR for the intensive intervention vs usual care, regarding the primary efficacy end point at the study end was 0.68 (95% CI, 0.32-1.47; P = .33). The P values for the end points were calculated with the use of the Cox proportional hazards model.

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Table Graphic Jump LocationTable 2. Overall Efficacy Profile of Intervention vs Usual Care at the 3-Year Follow-upa

The intensive intervention decreased the other events in the primary end point to a variable extent and nonsignificantly (P values range from .22 to .67), the benefit ranging from 9% reduction of the risk of undergoing a percutaneous coronary intervention (PCI) procedure to 28% reduction of the risk of hospitalization for heart failure.

LIFESTYLE HABITS

Lifestyle habits were similar in the 2 groups at baseline and improved in both groups during the study. The improvement was, however, significantly larger (<.01) in the intervention group for the scores for physical activity, stress, and dietary habits (Figure 3).

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Figure 3.

Lifestyle changes over 3 years for the intervention and the usual care groups. A, Physical activity score (range, 3.0-12.0). Time effect, <.001; time × treatment,  = .01. B, Dietary habits, showing the rate of patients in the highest quartile (a score of ≥19.0 indicates a Mediterranean-like diet). Time effect, <.001; time × treatment, <.001. C, Stress score, showing the rate of patients in the lowest quartile (a score of ≤14.0 indicates a better self/stress management). Time effect, <.001; time × treatment, <.001.

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At baseline, the mean (SD) scores for physical activity were 6.7 (2.5) and 6.6 (2.4) in the intervention and usual care groups, respectively. At 6 months, it increased by 24.3% (mean score, 7.5 [2.2]) in the intervention group and by 18.2% (7.1 [2.3]) in the usual care group (Figure 3). Therefore, the 6-month score for physical activity was 6.1% higher in the intervention group (P < .01). The difference in the level of physical activity from baseline between the 2 groups was maintained throughout the study (23.8% vs 18.8%; difference, 5%; P = .01).

Overall, 26.1% of patients had Mediterranean-like dietary habits (score >19.0) at baseline, which rose to 59.6% at 6 months. At baseline, the mean (SD) dietary score was 16.6 (2.8) in the intensive group and 16.6 (2.7) in the usual care group. At 6 months, it increased by 18% (mean score, 19.1 [2.2]) in the intervention group and 14.1% (18.6 [2.3]) in the usual care group. Therefore, the 6-month dietary score was 3.9% higher in the intervention group than in the usual care group (P < .001). The difference in dietary habits from baseline between the 2 groups was maintained throughout the study (17.9% vs 14.5%; difference, 3.4%; P < .001), the rate of patients with Mediterranean-like diet (score >19.0) being higher in the intervention group than in the control group (P < .001) (Figure 3).

Compared with baseline values, the percentage of subjects with better self/stress management (score <14.0) almost doubled at 6 months in both groups (48.1% vs 40.9%). At baseline, the mean (SD) scores for self/stress management were 16.3 (3.8) and 16.2 (3.8) in the intervention and usual care groups, respectively. At 6 months, this figure decreased by 12.1% (14.0 [3.4]) in the intervention group and 8.3% (14.5 [3.6]) in the usual care group. Therefore, the 6-month score for self/stress management adjusted for baseline was 3.8% lower in the intervention group (P < .001). The difference in scores from baseline between the 2 groups was maintained throughout the study (14.1% vs 9.6%; difference, 4.5%; P < .001). Similarly, the rate of patients with better self/stress management (score <14.0) was higher in the intervention group (P < .001) (Figure 3).

At 6 months, the differences in levels of total blood cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides between the 2 groups were −2.3% ( = .01), 2.4% ( = .06), −2.0% (P = .02), and −4.2% ( = .02), respectively (Figure 4). When we compared the mean levels in the 2 arms during the course of the study, the differences between the 2 groups in levels of total blood cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were −1.5% (P = .04), 2.5% (P = .25), −1.2% (P = .12), and −3.2% (P = .19), respectively (Figure 4). Glycemic levels increased slightly over time in both groups to the same extent (data not shown). The HbA1c levels (Figure 5) showed no change in either group.

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Figure 4.

Blood lipid concentrations during the 3 years of the study. A, Total cholesterol level. Time effect, <.001; time × treatment, P = .04. B, Low-density lipoprotein (LDL) cholesterol level. Time effect, P = .003; time × treatment, P = .12. C, High-density lipoprotein (HDL) cholesterol level. Time effect, <.001; time × treatment, P = .25. D, Triglyceride level. Time effect, <.001; time × treatment, P = .19. To convert total, LDL, and HDL cholesterol to millimoles per liter, multiply by 0.0259; to convert triglycerides to millimoles per liter, multiply by 0.0113.

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Figure 5.

Changes in risk factors over 3 years for the intervention and the usual care groups. A, Hemoglobin A1c (HbA1c) levels. Time effect, <.97; time × treatment, P = .19. B, Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Time effect, <.001; time × treatment, P = .03. C, Smoking habits, showing the rate of smoking discontinuation among smokers at study entry. Time effect, <.001; time × treatment, P = .60. D, Systolic blood pressure (SBP), showing the rate of patients at target according to the American Heart Association/American College of Cardiology guidelines.5 Time effect, <.001; time × treatment, P = .39.

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At baseline, the mean (SD) BMIs were 26.5 (3.5) and 26.6 (3.6) in the intervention and usual care groups, respectively. At 6 months, it increased by 0.7% (26.6 [3.5]) in the intervention group and 0.9% (26.8 [3.5]) in the usual care group (Figure 5); that is, there was a 0.2% lower increase in BMI in the intervention group (P = .17). During the course of the study, BMI increased by 1.7% and 2.1% in the intervention and usual care groups, respectively, a difference that was statistically significant (0.4%; P = .03).

At 6 months, smoking was significantly more likely to have been discontinued in the intensive group than in the usual care group (80.2% vs 75.1%; P = .02). When we compared the percentage of quitters over the whole course of the study, the efficacy of the intervention against smoking declined, and eventually the absolute difference between the 2 groups was “only” 4.2% (P = .60).

Compared with the usual care group, the intervention group more frequently reached the blood pressure targets at 6 months (62.4% vs 59.5%) and at the end of the study (59.9% vs 55.8%), although the difference between the 2 groups was not statistically significant (Figure 5). The use of medications at baseline was similar in the 2 groups. During follow-up, a progressive decline in the rate of use of aspirin, β-blockers, and ACE inhibitors was seen in both groups (Figure 6). Such reduced prescription was more apparent in the usual care group. At the end of the study, the prescription of ACE inhibitors was significantly higher (P = .02) in the intervention group than in the usual care group. The prescription of statins increased notably during the study, and at the end it was significantly higher (P < .001) in the intervention group (84.2%) than in the usual care group (79.1%).

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Figure 6.

Secondary prevention drug prescription in the intervention and the usual care groups. A, Aspirin use. Time effect, <.09; time × treatment, P = .37. B, Statins use. Time effect, <.001; time × treatment, P = .001. C, Angiotensin-converting enzyme inhibitor use. Time effect, <.001; time × treatment, P = .001. D, β-Blocker use. Time effect, <.01; time × treatment, P = .86.

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The GOSPEL Study was designed to test a long-term preventive strategy after MI as well as to establish a high-level standard for secondary prevention. After 3 years, the integrated, multifactorial, reinforced approach proved effective in countering the risk factors and medication adherence deterioration over time and was able to induce a considerable improvement in lifestyle habits. In line with such results, all the clinical end points were reduced by the intensive intervention. The primary end point was decreased nonsignificantly by 12% ( = .12). However, the secondary outcome measures were significantly and importantly reduced: CV mortality, nonfatal MI, and stroke by 33% ( = .02) and cardiac death plus nonfatal MI by 36% ( = .02). In addition, total stroke and total mortality were decreased by 32% and 21%, respectively. The extent of the reduction for the individual events included in the primary end point varied from a statistically significant 48% (< .01) risk reduction for MI (1.4% vs 2.7%) to a nonsignificant 9% ( = .39) relative risk reduction for PCI procedures (8.9% vs 9.8%).

The absence of a formal statistical significance for the primary study end point is not surprising. First, the incidence of the primary end point was much lower than expected (17% instead of 30%), probably because of the recent changes of therapy after MI in this population compared with the GISSI-Prevenzione population, which had been recruited almost 10 years before the start of the GOSPEL Study.25 Second, the primary study end point was a combination of hard, but relatively rare events, such as nonfatal MI, the risk of which was halved, and PCI and CABG procedures, which were by far the most prevalent events but had a nonsignificant 10% reduction ( = .39 and  = .60, respectively). Third, the rate of smoking cessation in our population of patients followed in cardiac rehabilitation centers is greater than that observed in the United States, and such a high background rate of smoking cessation may have minimized the potential effects of the intervention.

In any case, to our knowledge this is the first clinical trial showing, in a large sample of more than 3200 patients who experienced an MI, that an integrated, multifactorial, reinforced, and individually tailored secondary prevention program is effective in reducing major CV events. The reliability of this benefit is corroborated by the parallel benefit in preventing the long-term deterioration of several risk factors and lifestyle behaviors. Indeed, a greater proportion of patients in the intervention group achieved the expected targets for physical activity, healthy diet, stress management, weight reduction, triglyceride and HDL cholesterol levels, and blood pressure.

The GOSPEL Study results on the time-related worsening of the management of cardiac risk factors in CHD are consistent with those of prior studies and confirm that the gains for risk factors and lifestyle behavior achieved with the initial CRP in patients who experienced an MI are not maintained over the course of time.7,8,1013 Discontinuation of cardioprotective medications was also a common feature found in the first year after completion of CRP. Although international guidelines strongly recommend actions to reinforce the therapeutic alliance between patients and physicians,25 the level of secondary prevention is far from optimal.1,3,7,9,11,12 The positive changes in medication use we observed in the intervention group were relevant, although not massive and not always statistically significant, and included a larger use of aspirin, ACE inhibitors, and β-blockers. Of note, the rate of prescription of statins at 3 years was remarkably high in both groups (intervention group, 84.2%; usual care group, 79.1%).

Several potential limitations warrant mention. The GOSPEL Study enrolled a broad, relatively low-risk population, with only a small proportion of patients either older than 70 years or with an echocardiogram-documented ejection fraction of less than 40%, and most of these had undergone revascularization after MI. The usual care group in the GOSPEL Study does not represent the real world of patients with recent MI because most patients in the real world do not receive standard CRP after acute MI. However, the GOSPEL trial was aimed at comparing 2 different rehabilitation strategies, not post-MI rehabilitation vs post-MI abandon of patients. Accordingly, it is possible that the annual assessment visits provided to the patients allocated to usual care (which are not routine in clinical practice) may have improved the prescription of medications and adoption of correct lifestyle habits, hence decreasing post-MI risk and so possibly downplaying the benefit of the intervention. The proportion of patients lost to follow-up and/or who dropped out of the study could seem high, but the peculiarity of the study, necessitating compliance to demanding lifestyle interventions, such as maintenance exercise, should be kept in mind. Moreover, a systematic external monitoring aimed at rescuing nonattendant patients was not implemented because this would have been inherently in contrast with an intervention program based on the convinced cooperation of the patients. These patients were maintained in the analysis, gave their contribution to the study person-time, and were right-censored at the point at which their last clinical information was known to the investigators. In any case, the proportion of patients lost to follow-up or withdrawn from the study was the same in the 2 groups. Therefore, this factor was probably random with respect to the outcome.

A prolongation of the follow-up would have increased the rate of events and the power of the study to observe a long-term benefit on atherothrombotic events in the intervention group. However, the GOSPEL Study was a pragmatic study, promoted by a scientific association, funded by the industry only to assure its coordination, and conducted in the framework of clinical practice within a nation-wide hospital network. Considering this scenario, follow-up prolongation to increase the rate of study events was discussed by the steering committee but was considered unfeasible and therefore not implemented.

Misclassification of lifestyle exposures may have occurred. Because data were collected prospectively, such errors would likely be random with respect to the outcome and would cause, if anything, underestimation of the observed associations. Moreover, because of the more intensive educational intervention, there may have been a stronger tendency for patients in this group to give positive answers on the lifestyle questionnaires than those in the usual care group. Finally, some of the study secondary end points were self-reported and were not colzlected in an otherwise verifiable fashion.

In conclusion, the nonsignificant reduction of the primary end point, the significant reduction of major CV events, the reduction of the other clinical end points, the relevant improvement of lifestyle habits, CV risk factors, and prescription of pharmacological treatments all indicate the importance of an intensive, comprehensive, long-term secondary prevention program after MI. To our knowledge, the GOSPEL Study is the first large-scale trial to demonstrate that such a multifactorial continued reinforced intervention following MI is effective.

Correspondence: Pantaleo Giannuzzi, MD, Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Via La Marmora 34, 50121 Florence, Italy (pantaleo.giannuzzi@fsm.it).

Accepted for Publication: April 21, 2008.

Author Contributions: Dr Marchioli had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Giannuzzi, Temporelli, Maggioni, Balestroni, Ceci, Chieffo, Gattone, Griffo, Schweiger, Tavazzi, Urbinati, and Vanuzzo approved the final version of the manuscript. Study concept and design: Giannuzzi, Temporelli, Marchioli, Maggioni, Balestroni, Ceci, Gattone, Griffo, Schweiger, Tavazzi, Urbinati, Valagussa, and Vanuzzo. Acquisition of data: Giannuzzi, Temporelli, Chieffo, Valagussa, and Urbinati. Analysis and interpretation of data: Giannuzzi, Temporelli, Marchioli, Maggioni, and Urbinati. Drafting of the manuscript: Giannuzzi, Temporelli, and Marchioli. Critical revision of the manuscript for important intellectual content: Giannuzzi, Temporelli, Marchioli, Maggioni, Balestroni, Ceci, Chieffo, Gattone, Griffo, Schweiger, Tavazzi, Urbinati, Valagussa, and Vanuzzo. Statistical analysis: Giannuzzi, Temporelli, Marchioli, and Vanuzzo. Obtained funding: Giannuzzi, Maggioni, and Valagussa. Administrative, technical, and material support: Giannuzzi, Temporelli, and Urbinati. Study supervision: Giannuzzi, Temporelli, Marchioli, Maggioni, Chieffo, Gattone, Griffo, Schweiger, Valagussa, and Urbinati.

GOSPEL Investigators:Steering Committee: P. Giannuzzi (chairman), V. Ceci, C. Chieffo, M. Gattone, R. Griffo, R. Marchioli, C. Schweiger, L. Tavazzi, S. Urbinati, F. Valagussa, and D. Vanuzzo. Executive Committee: P. Giannuzzi, A. P. Maggioni, M. Gattone, R. Griffo, and P. L. Temporelli. Participating Centers and Investigators: Ala (D. Girardini and G. Francesconi), Aosta (M. Vona), Arco (R. Santoni and C. Sarno), Arenzano (R. Griffo and P. Calisi), Arezzo (M. Forzoni and L. Boncompagni), Aurisina (G. Tabouret and U. Canci), Avellino (G. Rosato and G. Stanco), Bellano (G. Gullace and C. Carbone), Bergamo (A. Gavazzi and D. Mazzoleni), Bologna (G. Pinelli and S. Urbinati), Bozzolo (R. Frizzelli and O. Tortelli), Camposampiero (A. Pantaleoni and E. Mantovani), Casarano (G. Pettinati and G. Storti), Caserta (C. Chieffo and C. Riccio), Cassano Delle Murge (D. Scrutinio and A. Passantino), Castelnuovo ne’ Monti (U. Guiducci and G. Zobbi), Catania Ospedale Ascoli-Tomaselli (D. Vanaria and P. Barbanti), Catania Ospedale Cannizzaro (V. Carini and R. Coco), Catanzaro (G. Borrello and M. L. Mazza), Cecina (F. Chiesa and C. Sansoni), Cesano Boscone (E. Morbelli and L. Rossi), Chieti (C. Ciglia and P. Di Giovanni), Cittá di Castello (M. Cocchieri and V. Dò), Como (A. Trudu and D. Albonico), Correggio (S. Bendinelli and E. Iori), Cotignola (G. Balestra and N. Giacometti), Cremona (S. Coppetti and S. Priori), Firenze (G. Masotti and F. Fattirolli), Foligno (L. Meniconi and P. Paolucci), Gazzaniga (C. Malinverni and F. Quarenghi), Gorizia (A. Fontanelli and R. Marini), Gualdo Tadino (S. Mandorla and M. Provvidenza), Gussago (A. Giordano and F. De Giuli), Lucca (L. Odoguardi and S. Barsotti), Lugano (T. Moccetti and A. Molteni), Merate (F. Mauri and G. Lecchi), Mezzolombardo (R. Bettini and A. Bertoldi), Milano Istituti Clinici di Perfezionamento, Centro Traumatologico Ortopedico (R. Zanettini and P. Centeleghe), Milano Pio Albergo Trivulzio (S. Corallo and M. L. Rainoldi), Milano Fondazione Don Carlo Gnocchi (M. Ferratini and M. Tavanelli), Milano Ospedale San Luca (G. Leonetti and G. Malfatto), Mirano (P. Pascotto and A. Zanocco), Montebelluna (R. Buchberger and G. Masaro), Montescano (F. Cobelli and G. Riccardi), Monza (F. Valagussa and L. Sala), Mormanno (G. Musca and M. A. Cauteruccio), Napoli Federico II (C. Vigorito and F. Giallauria), Napol Vincenzo Monaldi (N. Mininni and P. Morra), Palermo (A. Castello and F. M. Sarullo), Passirana-Rho (C. Schweiger and D. Castelli), Pavia (R. Tramarin and M. De Salvo), Perugia Azienda Ospedaliera (C. Porcellati and F. Giovagnoni), Perugia Azienda Sanitaria Locale 2 (P. F. Anniboletti and M. G. Calisti), Pescia (W. Vergoni and L. Iacopetti), Ponte dell’ Olio (F. Zelaschi and S. D’Cruz), Potenza (A. Lopizzo and M. Caiazza), Rapallo (G. Gigli and J. Pastine), Reggio Calabria (G. Pulitanò and A. Ruggeri), Rimini (G. Piovaccari and P. Semprini), Rivolta d'Adda (G. Zavatteri and T. Diaco), Roma Ospedale Santo Spirito (V. Ceci and F. Lumia), Roma Ospedale C. Forlanini (A. M. Tamiz and G. Oliva), Roma Villa Betania (A. Galati and A. Picelli), Romano Lombardo (F. Pesciatini and R. Bosco), S. Omero (G. Marcellini and E. Zanchè), Sacile (G. Martin and S. Masutti), San Donà Di Piave (L. Milani and G. M. Pizzolato), Sondalo (G. Occhi and N. Partesana), Taranto (N. Baldi and G. Polimeni), Telese Terme (G. Furgi and A. Nicolino), Torino Ospedale Mauriziano (R. Bevilacqua and B. Ingignoli), Torino Ospedale Evangelico Valdese (N. Massobrio and G. Avogliero), Tradate (R. Pedretti and R. Vaninetti), Trebisacce (L. Donnangelo and M. Chiatto), Trieste (P. Gori), Veruno (P. Giannuzzi and P. L. Temporelli), and Vicenza (A. Fontanelli and R. Garbin).

Financial Disclosure: None reported.

Funding/Support: The GOSPEL Study was supported by Società Prodotti Antibiotici with an unrestricted research grant.

Role of the Sponsor: The funding source played no role in the conception, design, or conduct of the study; in the analysis or interpretation of the data; in the writing of this article; or in the decision to submit the manuscript for publication.

Additional Contributions: The GOSPEL Study was promoted by the Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Florence, Italy, and endorsed by the Gruppo Italiano di Cardiologia Riabilitativa e Preventiva. We thank the GOSPEL Investigators and the patients who participated in the GOSPEL trial. Rosamaria Marfisi and Donata Lucci contributed to the statistical analysis, and the technical and secretarial personnel of the ANMCO Centro Studi in Florence provided assistance. We extend our deepest thanks for the many contributions and kind friendship of Dr Valagussa, who passed away in December 2006. The GOSPEL Study steering committee had the full responsibility for design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.

Ades  PA Cardiac rehabilitation and secondary prevention of coronary artery disease. N Engl J Med 2001;345 (12) 892- 902
PubMed Link to Article
Balady  GJAdes  PAWilliams  MA  et al.  Core components of cardiac/secondary prevention programs. Circulation 2000;102 (9) 1069- 1073
PubMed Link to Article
Giannuzzi  PSaner  HBjörnstad  H  et al.  Secondary prevention through cardiac rehabilitation: position paper of the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology. Eur Heart J 2003;24 (13) 1273- 1278
PubMed Link to Article
De Backer  GAmbrosioni  EBorch-Johnsen  K  et al. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice, European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003;24 (17) 1601- 1610
PubMed Link to Article
Smith  SCAllen  JBlair  SN  et al.  AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation 2006;113 (19) 2363- 2372
PubMed Link to Article
Balady  GJWilliams  MAAdes  PA  et al.  Core components of cardiac rehabilitation/secondary prevention programs: 2007 update: a scientific statement from the American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee, the Council on Clinical Cardiology; the Councils on Cardiovascular Nursing, Epidemiology and Prevention, and Nutrition, Physical Activity, and Metabolism; and the American Association of Cardiovascular and Pulmonary Rehabilitation. Circulation 2007;115 (20) 2675- 2682
PubMed Link to Article
EUROASPIRE Study Group; EUROASPIRE I and II Group, European Action on Secondary Prevention by Intervention to Reduce Events: clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. Lancet 2001;357 (9261) 995- 1001
PubMed Link to Article
Kotseva  KWood  DADe Bacquer  DHeidrich  JDe Backer  Gfor EUROASPIRE II Study Group, Cardiac rehabilitation for coronary patients: lifestyle, risk factor and therapeutic management: results from the EUROASPIRE II survey. Eur Heart J Suppl 2004;6 ((suppl J)) J17- J26
Link to Article
Williams  MAAdes  PAHamm  LF  et al.  Clinical evidence for a health benefit from cardiac rehabilitation: an update. Am Heart J 2006;152 (5) 835- 841
PubMed Link to Article
Willich  SNMuller-Nordhorn  JKulig  M  et al.  Cardiac risk factors, medication, and recurrent clinical events after acute coronary disease: a prospective cohort study. Eur Heart J 2001;22 (4) 307- 313
PubMed Link to Article
Lear  SAIgnaszewski  ALinden  W  et al.  The Extensive Lifestyle Management Intervention (ELMI) following cardiac rehabilitation trial. Eur Heart J 2003;24 (21) 1920- 1927
PubMed Link to Article
De Velasco  JARodriguez  JARidocci  FAznar  J Action to improve secondary prevention in coronary artery disease patients: one-year follow-up of a shared care programme. Eur Heart J Suppl 2004;6 ((suppl J)) J27- J32
Lear  SASpinelli  JJLinden  W  et al.  The Extensive Lifestyle Management Intervention (ELMI) after cardiac rehabilitation: a 4-year randomized controlled trial. Am Heart J 2006;152 (2) 333- 339
PubMed Link to Article
Moore  SMCharvat  JMGordon  NH  et al.  Effects of a CHANGE intervention to increase exercise maintenance following cardiac events. Ann Behav Med 2006;31 (1) 53- 62
PubMed Link to Article
Ho  PMSpertus  JAMasoudi  FA  et al.  Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006;166 (17) 1842- 1847
PubMed Link to Article
Newby  LKLaPointe  NMChen  AY  et al.  Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation 2006;113 (2) 203- 212
PubMed Link to Article
Giannuzzi  PTemporelli  PLMaggioni  AP  et al. for GOSPEL Investigators, Global secondary prevention strategies to limit event recurrence after myocardial infarction: the GOSPEL Study: a trial from the Italian Cardiac Rehabilitation Network: rationale and design. Eur J Cardiovasc Prev Rehabil 2005;12 (6) 555- 561
PubMed
Pyke  SDWood  DAKinmonth  AKLThompson  Sfor British Family Heart Study Group, Concordance of changes in coronary risk factors levels in couples following lifestyle intervention in the British Family Heart Study. Arch Fam Med 1997;6 (4) 354- 360
PubMed Link to Article
Knoops  KTde Groot  LCKromhout  D  et al.  Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the Hale project. JAMA 2004;292 (12) 1433- 1439
PubMed Link to Article
Wood  DAKotseva  KJennings  C  et al. for EuroAction Study Group, EUROACTION: a European Society of Cardiology demonstration project in preventive cardiology: a cluster randomised controlled trial of a multi-disciplinary preventive cardiology programme for coronary patients, asymptomatic high risk individuals and their families: summary of design, methodology and outcomes. Eur Heart J Suppl 2004;6 ((suppl J)) J3- J15
Link to Article
Thompson  PDBuchner  DPiña  IL  et al.  Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003;107 (24) 3109- 3116
PubMed Link to Article
Barzi  FWoodward  MMarfisi  RMTavazzi  LValagussa  FMarchioli  R Mediterranean diet and all-causes mortality after myocardial infarction: results from the GISSI-Prevenzione trial. Eur J Clin Nutr 2003;57 (4) 604- 611
PubMed Link to Article
Mozaffarian  DMarfisi  RLevantesi  G  et al.  Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors. Lancet 2007;370 (9588) 667- 675
PubMed Link to Article
Carinci  FNicolucci  ACiampi  A  et al. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico, Role of interactions between psychological and clinical factors in determining 6-month mortality among patients with acute myocardial infarction: application of recursive partitioning techniques to the GISSI-2 database. Eur Heart J 1997;18 (5) 835- 845
PubMed Link to Article
GISSI-Prevenzione Investigators, Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354 (9177) 447- 455
PubMed Link to Article
Macchia  ALevantesi  GFranzosi  MG  et al. GISSI-Prevenzione Investigators, Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids. Eur J Heart Fail 2005;7 (5) 904- 909
PubMed Link to Article
Diggle  PJHeagerty  PLiang  KZeger  SLAnalysis of Longitudinal Data. Oxford, England Oxford University Press2002;
Littell  RCMilliken  GAStroup  WWWolfinger  RDSAS System for Mixed Models. Cary, NC SAS Institute Inc1996;
Sullivan  LMDukes  KALosina  L Tutorial in biostatistics: an introduction to hierarchical linear modeling. Stat Med 1999;18 (7) 855- 888
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Study flowchart.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Cumulative Kaplan-Meier estimates of the rates of key study end points during the follow-up period among 3241 patients with recent myocardial infarction (MI). A, Data for the primary composite end point (cardiovascular mortality, nonfatal MI, nonfatal stroke, and hospitalization for angina pectoris, heart failure, or urgent revascularization procedure). The hazard ratio (HR) for the intensive intervention, compared with usual care, for the primary efficacy end point at the study end was 0.88 (95% confidence interval [CI], 0.74-1.04; P = .12). B, Data for the secondary efficacy end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke). The HR for the intensive intervention, compared with usual care, for the primary efficacy end point at the study end was 0.67 (95% CI, 0.47-0.95; P = .02). C, Data for the secondary efficacy end point (cardiac death plus nonfatal MI). The HR for the intensive intervention, compared with usual care, for the primary efficacy end point at the study end was 0.64 (95% CI, 0.43-0.94; P = .02). D, Data for the secondary efficacy end point (fatal plus nonfatal stroke). The HR for the intensive intervention vs usual care, regarding the primary efficacy end point at the study end was 0.68 (95% CI, 0.32-1.47; P = .33). The P values for the end points were calculated with the use of the Cox proportional hazards model.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Lifestyle changes over 3 years for the intervention and the usual care groups. A, Physical activity score (range, 3.0-12.0). Time effect, <.001; time × treatment,  = .01. B, Dietary habits, showing the rate of patients in the highest quartile (a score of ≥19.0 indicates a Mediterranean-like diet). Time effect, <.001; time × treatment, <.001. C, Stress score, showing the rate of patients in the lowest quartile (a score of ≤14.0 indicates a better self/stress management). Time effect, <.001; time × treatment, <.001.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Blood lipid concentrations during the 3 years of the study. A, Total cholesterol level. Time effect, <.001; time × treatment, P = .04. B, Low-density lipoprotein (LDL) cholesterol level. Time effect, P = .003; time × treatment, P = .12. C, High-density lipoprotein (HDL) cholesterol level. Time effect, <.001; time × treatment, P = .25. D, Triglyceride level. Time effect, <.001; time × treatment, P = .19. To convert total, LDL, and HDL cholesterol to millimoles per liter, multiply by 0.0259; to convert triglycerides to millimoles per liter, multiply by 0.0113.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Changes in risk factors over 3 years for the intervention and the usual care groups. A, Hemoglobin A1c (HbA1c) levels. Time effect, <.97; time × treatment, P = .19. B, Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Time effect, <.001; time × treatment, P = .03. C, Smoking habits, showing the rate of smoking discontinuation among smokers at study entry. Time effect, <.001; time × treatment, P = .60. D, Systolic blood pressure (SBP), showing the rate of patients at target according to the American Heart Association/American College of Cardiology guidelines.5 Time effect, <.001; time × treatment, P = .39.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

Secondary prevention drug prescription in the intervention and the usual care groups. A, Aspirin use. Time effect, <.09; time × treatment, P = .37. B, Statins use. Time effect, <.001; time × treatment, P = .001. C, Angiotensin-converting enzyme inhibitor use. Time effect, <.001; time × treatment, P = .001. D, β-Blocker use. Time effect, <.01; time × treatment, P = .86.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Patients Who Were Randomly Assigneda
Table Graphic Jump LocationTable 2. Overall Efficacy Profile of Intervention vs Usual Care at the 3-Year Follow-upa

References

Ades  PA Cardiac rehabilitation and secondary prevention of coronary artery disease. N Engl J Med 2001;345 (12) 892- 902
PubMed Link to Article
Balady  GJAdes  PAWilliams  MA  et al.  Core components of cardiac/secondary prevention programs. Circulation 2000;102 (9) 1069- 1073
PubMed Link to Article
Giannuzzi  PSaner  HBjörnstad  H  et al.  Secondary prevention through cardiac rehabilitation: position paper of the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology. Eur Heart J 2003;24 (13) 1273- 1278
PubMed Link to Article
De Backer  GAmbrosioni  EBorch-Johnsen  K  et al. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice, European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003;24 (17) 1601- 1610
PubMed Link to Article
Smith  SCAllen  JBlair  SN  et al.  AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. Circulation 2006;113 (19) 2363- 2372
PubMed Link to Article
Balady  GJWilliams  MAAdes  PA  et al.  Core components of cardiac rehabilitation/secondary prevention programs: 2007 update: a scientific statement from the American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee, the Council on Clinical Cardiology; the Councils on Cardiovascular Nursing, Epidemiology and Prevention, and Nutrition, Physical Activity, and Metabolism; and the American Association of Cardiovascular and Pulmonary Rehabilitation. Circulation 2007;115 (20) 2675- 2682
PubMed Link to Article
EUROASPIRE Study Group; EUROASPIRE I and II Group, European Action on Secondary Prevention by Intervention to Reduce Events: clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. Lancet 2001;357 (9261) 995- 1001
PubMed Link to Article
Kotseva  KWood  DADe Bacquer  DHeidrich  JDe Backer  Gfor EUROASPIRE II Study Group, Cardiac rehabilitation for coronary patients: lifestyle, risk factor and therapeutic management: results from the EUROASPIRE II survey. Eur Heart J Suppl 2004;6 ((suppl J)) J17- J26
Link to Article
Williams  MAAdes  PAHamm  LF  et al.  Clinical evidence for a health benefit from cardiac rehabilitation: an update. Am Heart J 2006;152 (5) 835- 841
PubMed Link to Article
Willich  SNMuller-Nordhorn  JKulig  M  et al.  Cardiac risk factors, medication, and recurrent clinical events after acute coronary disease: a prospective cohort study. Eur Heart J 2001;22 (4) 307- 313
PubMed Link to Article
Lear  SAIgnaszewski  ALinden  W  et al.  The Extensive Lifestyle Management Intervention (ELMI) following cardiac rehabilitation trial. Eur Heart J 2003;24 (21) 1920- 1927
PubMed Link to Article
De Velasco  JARodriguez  JARidocci  FAznar  J Action to improve secondary prevention in coronary artery disease patients: one-year follow-up of a shared care programme. Eur Heart J Suppl 2004;6 ((suppl J)) J27- J32
Lear  SASpinelli  JJLinden  W  et al.  The Extensive Lifestyle Management Intervention (ELMI) after cardiac rehabilitation: a 4-year randomized controlled trial. Am Heart J 2006;152 (2) 333- 339
PubMed Link to Article
Moore  SMCharvat  JMGordon  NH  et al.  Effects of a CHANGE intervention to increase exercise maintenance following cardiac events. Ann Behav Med 2006;31 (1) 53- 62
PubMed Link to Article
Ho  PMSpertus  JAMasoudi  FA  et al.  Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006;166 (17) 1842- 1847
PubMed Link to Article
Newby  LKLaPointe  NMChen  AY  et al.  Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation 2006;113 (2) 203- 212
PubMed Link to Article
Giannuzzi  PTemporelli  PLMaggioni  AP  et al. for GOSPEL Investigators, Global secondary prevention strategies to limit event recurrence after myocardial infarction: the GOSPEL Study: a trial from the Italian Cardiac Rehabilitation Network: rationale and design. Eur J Cardiovasc Prev Rehabil 2005;12 (6) 555- 561
PubMed
Pyke  SDWood  DAKinmonth  AKLThompson  Sfor British Family Heart Study Group, Concordance of changes in coronary risk factors levels in couples following lifestyle intervention in the British Family Heart Study. Arch Fam Med 1997;6 (4) 354- 360
PubMed Link to Article
Knoops  KTde Groot  LCKromhout  D  et al.  Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the Hale project. JAMA 2004;292 (12) 1433- 1439
PubMed Link to Article
Wood  DAKotseva  KJennings  C  et al. for EuroAction Study Group, EUROACTION: a European Society of Cardiology demonstration project in preventive cardiology: a cluster randomised controlled trial of a multi-disciplinary preventive cardiology programme for coronary patients, asymptomatic high risk individuals and their families: summary of design, methodology and outcomes. Eur Heart J Suppl 2004;6 ((suppl J)) J3- J15
Link to Article
Thompson  PDBuchner  DPiña  IL  et al.  Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003;107 (24) 3109- 3116
PubMed Link to Article
Barzi  FWoodward  MMarfisi  RMTavazzi  LValagussa  FMarchioli  R Mediterranean diet and all-causes mortality after myocardial infarction: results from the GISSI-Prevenzione trial. Eur J Clin Nutr 2003;57 (4) 604- 611
PubMed Link to Article
Mozaffarian  DMarfisi  RLevantesi  G  et al.  Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors. Lancet 2007;370 (9588) 667- 675
PubMed Link to Article
Carinci  FNicolucci  ACiampi  A  et al. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico, Role of interactions between psychological and clinical factors in determining 6-month mortality among patients with acute myocardial infarction: application of recursive partitioning techniques to the GISSI-2 database. Eur Heart J 1997;18 (5) 835- 845
PubMed Link to Article
GISSI-Prevenzione Investigators, Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354 (9177) 447- 455
PubMed Link to Article
Macchia  ALevantesi  GFranzosi  MG  et al. GISSI-Prevenzione Investigators, Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids. Eur J Heart Fail 2005;7 (5) 904- 909
PubMed Link to Article
Diggle  PJHeagerty  PLiang  KZeger  SLAnalysis of Longitudinal Data. Oxford, England Oxford University Press2002;
Littell  RCMilliken  GAStroup  WWWolfinger  RDSAS System for Mixed Models. Cary, NC SAS Institute Inc1996;
Sullivan  LMDukes  KALosina  L Tutorial in biostatistics: an introduction to hierarchical linear modeling. Stat Med 1999;18 (7) 855- 888
PubMed Link to Article

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