The Lancet：好的身体素质可以增强他汀类药物的疗效

Articles www.thelancet.com Published online November 28, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61426-3 1 Published Online November 28, 2012 http://dx.doi.org/10.1016/ S0140-6736(12)61426-3 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(12)61804-2 Cardiology Department, Veterans Affairs Medical Center, Washington DC, USA (Prof P F Kokkinos PhD, C Faselis MD, D Panagiotakos PhD, M Doumas MD); Georgetown University School of Medicine, Washington DC, USA (Prof P F Kokkinos); George Washington University School of Medicine, Washington DC, USA (Prof P F Kokkinos, C Faselis); Cardiology Division, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA (Prof J Myers PhD); and Stanford University, Stanford, CA, USA (Prof J Myers) Correspondence to: Prof Peter F Kokkinos, Veterans Affairs Medical Center, Cardiology Division, 50 Irving Street NW, Washington DC, 20422, USA peter.kokkinos@va.gov Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study Peter F Kokkinos, Charles Faselis, Jonathan Myers, Demosthenes Panagiotakos, Michael Doumas Summary Background Statins are commonly prescribed for management of dyslipidaemia and cardiovascular disease. Increased fitness is also associated with low mortality and is recommended as an essential part of promoting health. However, little information exists about the combined effects of fitness and statin treatment on all-cause mortality. We assessed the combined effects of statin treatment and fitness on all-cause mortality risk. Methods In this prospective cohort study, we included dyslipidaemic veterans from Veterans Affairs Medical Centers in Palo Alto, CA, and Washington DC, USA, who had had an exercise tolerance test between 1986, and 2011. We assigned participants to one of four fitness categories based on peak metabolic equivalents (MET) achieved during exercise test and eight categories based on fitness status and statin treatment. The primary endpoint was all-cause mortality adjusted for age, body-mass index, ethnic origin, sex, history of cardiovascular disease, cardiovascular drugs, and cardiovascular risk factors. We assessed mortality from Veteran’s Affairs’ records on Dec 31, 2011. We compared groups with Cox proportional hazard model. Findings We assessed 10 043 participants (mean age 58·8 years, SD 10·9 years). During a median follow-up of 10·0 years (IQR 6·0–14·2), 2318 patients died, with an average yearly mortality rate of 22 deaths per 1000 person-years. Mortality risk was 18·5% (935/5046) in people taking statins versus 27·7% (1386/4997) in those not taking statins (p<0·0001). In patients who took statins, mortality risk decreased as fitness increased; for highly fit individuals (>9 MET; n=694), the hazard ratio (HR) was 0·30 (95% CI 0·21–0·41; p<0·0001) compared with least fit (≤5 METs) patients (HR 1; n=1060). For those not treated with statins, the HR for least fit participants (n=1024) was 1·35 (95% CI 1·17–1·54; p<0·0001) and progressively decreased to 0·53 (95% CI 0·44–0·65; p<0·0001) for those in the highest fitness category (n=1498). Interpretation Statin treatment and increased fitness are independently associated with low mortality among dyslipidaemic individuals. The combination of statin treatment and increased fitness resulted in substantially lower mortality risk than either alone, reinforcing the importance of physical activity for individuals with dyslipidaemia. Funding None. Introduction Results of several clinical trials have shown that statin treatment substantially reduces morbidity and mortality of individuals with coronary heart disease.1–3 On the basis on these findings, the Adult Treatment Panel 3 and other expert panels have issued guidelines4 for statin treatment of patients with established coronary heart disease.5 Trials also suggest that statin treatment provides health benefits for individuals with high risk of cardiovascular disease who do not have coronary heart disease.6–9 Expert panels on management of lipids have also emphasised the importance of lifestyle changes for reduction of cardiovascular risk.4,5 These recom­ men dations are based on evidence from large epidemiological studies. Data from these studies show inverse, graded, independent, and robust associations between physical activity (fitness) and mortality risk in apparently healthy participants10–16 and in patients with cardiovascular disease, irrespective of age, sex, or comorbidities.14,17–20 Mortality risk is highest for patients with low fitness; risk decreases as fitness increases irrespective of sex, presence of other risk factors, or age.14,15,17,19–21 Although a healthy lifestyle—including physical activity and fitness—is promoted as an essential component for prevention and management of coronary heart disease, little data are available regarding the combined health benefits of fitness and statin treatment. Furthermore, for dyslipidaemic patients who cannot take statins, whether increased mortality risk can be abated by increased fitness is unclear. We assessed the separate and combined effects of statin treatment and exercise capacity on all­cause mortality risk in veterans with dyslipidaemia. Methods Study design and patients This prospective cohort study included patients from the Veterans Affairs Medical Centers in Washington, DC, USA and Palo Alto, CA, USA. The cohort was taken from a database of more than 20 000 veterans who had dys lipi­ daemia (defined by the International Classifica tion of Diseases) and who had a symptom­limited exercise toler­ ance test between 1986, and 2011. The test was adminis­ tered either as part of a routine assessment or to assess exercise­induced ischaemia. This information, along with the patient’s medical history, was electronically stored. Articles 2 www.thelancet.com Published online November 28, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61426-3 Exclusion criteria were: history of an implanted pace­ maker; development of left bundle branch block during the test; inability to complete the test because of musculoskeletal pain or impairments; exercise capacity less than 2 metabolic equivalents (MET); instability or need for emergency intervention; body­mass index less than 15·5 kg/m²; impaired chronotropic response to exercise; HIV/AIDS; and missing data. The study was approved by the institutional review board at each institution, and all participants gave written informed consent. Procedures Clinical characteristics and demographic and drug information were obtained from the patients’ electronic medical record before the exercise tolerance test. Each individual was asked to verify the information, including history of chronic disease, current treatments, and smoking habits. Bodyweight and height were assessed by a standardised scale and recorded before the test. Duration of statin treatment was based on the first and last date that statins were prescribed for each patient. Individuals were judged to be on statin treatment if these two dates were more than 3 months apart. The most recent assessments of lipid and lipoprotein con centrations represent post­statin treatment values. For patients not taking statins, the lipid assessment values before diagnosis of dyslipidaemia represent the first assessment and the most recent lipid assessment represents the final value. Exercise capacity was assessed by a standard treadmill test with the Bruce protocol at the centre in Washington DC, and by an individualised ramp protocol22 at the Palo Alto centre. Peak exercise time was recorded in minutes. Peak exercise capacity (in MET) was estimated with standardised equations on the basis of peak speed and grade for the ramp protocol22 and peak exercise time for the Bruce protocol.23 One MET was defined as the energy expended at rest, which is roughly equivalent to an oxygen consumption of 3·5 mL per kg of bodyweight per min. Participants were encouraged to exercise until volitional fatigue in the absence of symptoms or other indications for stopping.24 Use of handrails was allowed only if necessary for balance and safety. Age­predicted peak exercise heart rate was evaluated with a population­ specific equation.25 Drug regimens were not altered before testing. Entire cohort (n=10 043) Taking statins (n=5033) Not taking statins (n=5010) p value Age (years) 58·8 (10·9) 59·4 (10·4) 57·6 (11·3) <0·0001 Weight (kg) 90·5 (17·7) 92·4 (17·8) 88·5 (17·3) <0·0001 Body-mass index (kg/m²) 29·2 (5·2) 29·7 (5·3) 28·7 (5·2) <0·0001 Resting heart rate (beats per min) 71 (13) 71 (13) 71 (13) 0·76 Resting systolic blood pressure (mm Hg) 131 (20) 130 (20) 131 (21) 0·11 Resting diastolic blood pressure (mm Hg) 79 (12) 79 (12) 79 (12) 0·25 Peak MET 7·4 (2·6) 6·9 (1·9) 7·8 (3·0) <0·0001 Ethnic origin African-American 5192 (52%) 3346 (66%) 1846 (37%) <0·0001 White 4425 (44%) 1624 (32%) 2801 (56%) <0·0001 Other 426 (4%) 63 (1%) 363 (7%) <0·0001 History of cardiovascular disease 4198 (42%) 2980 (59%) 1218 (24%) <0·0001 Family history of cardiovascular disease 1687 (17%) 609 (12%) 1078 (22%) <0·0001 Current smoker 2222 (22%) 1266 (25%) 956 (19%) <0·0001 Hypertension 5500 (55%) 3032 (60%) 2468 (49%) <0·0001 Type 2 diabetes mellitus 3775 (38%) 2075 (41%) 1700 (34%) <0·0001 Drug treatments β blocker 1489 (15%) 860 (17%) 629 (13%) <0·0001 Calcium channel blockers 1773 (18%) 963 (19%) 810 (16%) <0·0001 Angiotensin-converting enzyme inhibitors 1869 (19%) 1249 (25%) 620 (12%) <0·0001 Angiotensin receptor blockers 232 (2%) 200 (4%) 32 (1%) <0·0001 Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers 1973 (20%) 1336 (26%) 637 (13%) <0·0001 Diuretics 1271 (13%) 1025 (20%) 246 (5%) <0·0001 Nitrates or vasodilators 546 (5%) 185 (4%) 361 (7%) <0·0001 Aspirin 668 (7%) 480 (10%) 188 (4%) <0·0001 Data are mean (SD) or n (%). p value calculated by Z test for ethnic origin, by χ² test for drug treatments and medical history (cardiovasular disease, hypertension, and diabetes mellitus), and by t test for of the remaining variables. MET=metabolic equivalents. Table 1: Baseline characteristics Articles www.thelancet.com Published online November 28, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61426-3 3 We created four fitness categories on the basis of peak MET. Patients with a peak MET value of 5·0 or less (the lowest 25th percentile of the MET values acheived) were classed as least fit; those with a peak MET value of 5·1–7·0 (26th–50th percentile) were classed as moderately fit; those with a peak MET value of 7·1–9·0 (51st–75th percentile) were classed as fit; and those with a peak MET value of more than 9·0 (>75th percentile) were classed as highly fit. We formed two groups (treated with statins and not treated with statins) within each fitness category, giving eight categories in total. The primary endpoint was death from any cause. Dates of death were first assessed from the database and verified from the Veterans Affairs Benefi ciary Identification and the Record Locator System File. This system is used to calculate benefits for relatives of deceased veterans and is 95% complete and accurate.26 Mortality was assessed on 31 Dec 31, 2011. Statistical analysis Follow­up time is presented as median with IQRs. We calculated mortality rate as the ratio of events to person­ years of follow­up. Continuous variables are presented as means and SDs and categorical variables as relative frequencies. We tested baseline associations between categorical variables with χ² or Z tests. We did one­way ANOVA and t tests to evaluate mean differences of normally distributed variables between individuals taking and not taking statins. We tested the assumption of equality of variances between groups by Levene’s test, and the assumption of normality with probability–probability plots. We calculated hazard ratios (HRs) for all­cause mortality for the four fitness categories, the two statin treatment categories, and the eight fitness–statin categories with Cox proportional hazard models. We also assessed first order interactions between statin treatment and fitness groups. For the four fitness categories, the least fit category was the reference group. For the statin treatment categories, no statin treatment was the refer ence group. For the eight fitness–statin categories, the least fit, treated with statins category was the reference group. We also used Cox proportional hazard models to assess risk in the eight fitness–statin categories. We adjusted analyses for age, body­mass index, ethnic origin, sex, history of cardiovascular disease, cardio vascular medications (angiotensin­converting enzyme inhibitors, angiotensin receptor blockers, β blockers, calcium channel blocker, diuretics, vasodilators), and cardio vascular disease risk factors (hypertension, type 2 diabetes mellitus, smoking). We tested assumption of proportionality for all Cox pro­ portional hazard analyses graphically, by plotting the cumulative hazards of the logarithms of the covariates; the proportionality assumption was fulfilled for each model. All hypotheses were two sided and p less than 0·05 was deemed statistically significant. We did all statistical analyses with SPSS (version 19.0). Role of the funding source There was no funding source for this study. The corres­ ponding author had full access to all data in the study and had final responsibility to submit it for publication. Patients treated with statins Patients not treated with statins Before statin treatment (n=2959) After statin treatment (n=2959) Mean difference (95% CI) p value Initial (n=1433) At follow-up (n=1433) Mean diffrence (95% CI) p value Total cholesterol (mmol/L) 6·1 (0·8) 4·4 (1·2) 1·7 (1·6 to 1·7) <0·0001 6·0 (0·8) 5·1 (1·1) 0·9 (0·8 to 0·9) <0·0001 Triglycerides (mmol/L) 1·6 (0·9) 1·5 (1·0) 0·2 (0·1 to 0·2) <0·0001 1·5 (0·9) 1·5 (0·8) 0·1 (0·0 to 0·2) 0·03 HDL cholesterol (mmol/L) 1·2 (0·3) 1·2 (0·3) 0·1 (0·0 to 0·1) <0·0001 1·2 (0·4) 1·2 (0·4) 0·0 (0·0 to 0·0) 0·22 LDL cholesterol (mmol/L) 4·2 (0·7) 2·6 (1·0) 1·6 (1·5 to 1·6) <0·0001 4·0 (0·8) 3·6 (0·9) 0·4 (0·4 to 0·5) <0·0001 Data are mean (SD) unless stated otherwise. p values calculated by paired t test. Table 2: Lipid and lipoprotein concentrations Patients (n) Deaths (n; %) Unadjusted HR (95% CI) Age-adjusted HR (95% CI) Fully adjusted HR (95% CI)* p value† Whole cohort (n=10 043) ≤5·0 MET 2084 920 (44%) 1 1 1 ·· 5·1–7·0 MET 2727 726 (27%) 0·61 (0·55–0·67) 0·68 (0·62–0·75) 0·70 (0·63–0·77) <0·0001 7·1–9·0 MET 3040 443 (15%) 0·34 (0·31–0·38) 0·48 (0·43–0·54) 0·50 (0·45–0·57) <0·0001 >9·0 MET 2192 229 (10%) 0·22 (0·19–0·25) 0·35 (0·30–0·40) 0·38 (0·32–0·44) <0·0001 Patients taking statins (n=5032) ≤5·0 MET 1060 389 (37%) 1 1 1 ·· 5·1–7·0 MET 1573 329 (21%) 0·56 (0·49–0·65) 0·64 (0·55–0·74) 0·64 (0·55–0·74) <0·0001 7·1–9·0 MET 1705 173 (10%) 0·28 (0·23–0·33) 0·40 (0·33–0·48) 0·41 (0·34–0·49) <0·0001 >9·0 MET 694 39 (6%) 0·17 (0·12–0·23) 0·29 (0·21–0·41) 0·32 (0·23–0·45) <0·0001 Patients not taking statins (n=5011) ≤5·0 MET 1024 531 (52%) 1 1 1 ·· 5·1–7·0 MET 1154 397 (34%) 0·65 (0·57–0·74) 0·72 (0·64–0·82) 0·74 (0·65–0·84) <0·0001 7·1–9·0 MET 1335 270 (20%) 0·40 (0·34–0·46) 0·56 (0·48–0·65) 0·57 (0·49–0·66) <0·0001 >9·0 MET 1498 190 (13%) 0·22 (0·18–0·25) 0·35 (0·29–0·41) 0·37 (0·31–0·44) <0·0001 Excluding people in the least fit category (≤5·0 MET) who died within 2 years of follow-up (n=9797) ≤5·0 MET 1968 804 (41%) 1 1 1 ·· 5·1–7·0 MET 2662 661 (25%) 0·64 (0·57–0·70) 0·70 (0·44–0·56) 0·70 (0·63–0·77) <0·0001 7·1–9·0 MET 2997 400 (13%) 0·35 (0·31–0·40) 0·50 (0·44–0·56) 0·50 (0·45–0·57) <0·0001 >9·0 MET 2170 207 (10%) 0·22 (0·19–0·26) 0·35 (0·30–0·41) 0·38 (0·32–0·44) <0·0001 HR=hazard ratio. MET=metabolic equivalents. *Adjusted for age, body-mass index, ethnic origin, sex, β blockers, calcium channel blockers, angiotensin-converting enzymes, angiotensin receptor blockers, aspirin, diuretics, history of smoking, history of cardiovascular disease, hypertension, and diabetes mellitus. †For fully adjusted HR. Table 3: Mortality risk by fitness Articles 4 www.thelancet.com Published online November 28, 2012 http://dx.doi.org/10.1016/S0140-6736(12)61426-3 Results We assessed 20 023 people for eligibility. We enrolled 10 043 veterans (9700 men and 343 women). 5192 were African­American (mean age 57·8 years, SD 10·7), 4425 were white (mean age 59·5 years, SD 10·9), and 426 were other (mean age 57·6 years, SD 11). Median follow­up was 10·0 years (IQR 6·0–14·2); providing 105 334 person­years. 2318 (23·1%) patients died (no data were missing), with an average yearly mortality of 22 deaths per 1000 person­years (95% CI 13–31). Patients not treated with statins had significantly higher mortality than did patients treated with statins (1386/4997 vs 935/5046 died; 27·7% vs 18·5%; p<0·0001). No interaction existed between site and METs (p=0·66) or ethnic origin and METs (p=0·40). Individuals taking statins tended to be older and had a higher body­mass index and lower exercise capacity than those not taking statins (table 1). The prevalences of cardiovascular disease, smoking, hypertension, type 2 diabetes mellitus, and use of β blockers, calcium chan ­ nel blockers, angiotensin­converting enzyme inhibitors, angiotensin receptor blockers, diuretics, and aspirin were also higher in patients taking statins than in those not taking statins. Family history of cardiovascular disease, and use of nitrates or vasodilators was higher in patients not taking statins than in those taking statins. Median duration of statin treatment was 70 months. For patients not treated with statins, median duration between the first and final lipid assessments was 51 months. Patients treated with statins had a significantly greater reduction in total cholesterol, LDL­cholesterol, HDL­cholesterol, and triglycerides than did those not taking statins (table 2). Significant predictors of all­cause mortality were: age (HR 1·05, 95% CI 1·04–1·05; p<0·0001), hypertension (1·22, 1·12–1·34; p<0·0001), smoking (1·26, 1·15–1·39; p<0·0001); type 2 diabetes (1·39, 1·27–1·51; p<0·0001), body­mass index (0·98, 0·97–0·99; p=0·001), and exercise capacity. For each 1 MET increase in exercise capacity, adjusted mortality decreased (HR 0·88, 95% CI 0·86–0·89; p<0·0001). Adjusted mortality risk was also significantly lower for patients taking statins than those not taking statins (0·65, 0·59–0·71; p<0·0001). The effect of exercise capacity was stronger in the statin treatment group. For each 1 MET increase in exercise capacity, the HR for adjusted mortality was 0·83 (95% CI 0·80–0·87; p<0·0001) for those taking statins compared with 0·89 (95% CI 0·87–0·91; p<0·0001) for those not taking statins. The interaction between fitness categories and statin treatment also significantly affected mortality risk (p=0·007). Table 3 and the figure show mortality risk across fitness categories. For the entire cohort in the final adjusted model, mortality risk progressively decreased as exercise capacity increased (table 3). Similarly, the adjusted risks for individuals treated with statins were progressively lower with increased exercise capacity. To account for the possibility that the higher mortality rates in the low fitness categories were caused by underlying diseases (such as cachexia or musculoskeletal or peripheral vascular conditions) and not low fitness per se (reverse causality), patients who died within the first 2 years of follow­up (n=246) were excluded and the analyses were repeated. The association between exercise capacity and mortality risk remained (p<0·0001 for all compa