- Email: [email protected]
Are Statins out in the COLD? The STATCOPE Trial
Canadian Journal of Cardiology 31 (2015) 970e973
Viewpoint
Are Statins out in the COLD? The STATCOPE Trial G.B. John Mancini, MD, FRCPC,a and Jeremy Road, MD, FRCPCb a
Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
b
Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
ABSTRACT
RESUM E
A cardiologist and respirologist examined the recent, neutral Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) for issues of relevance to cardiovascular risk reduction with statin medications. Although the potential benefit of the pleiotropic effects of statins on this inflammatory disease was not borne out, the effect over the longer term on total respiratory and cardiovascular morbidity and mortality remain unexplored. This study was unique as the only statin trial to date to use a national guideline (Adult Treatment Panel III) to exclude patients from the trial if at sufficient cardiovascular risk to warrant statin therapy. Furthermore, observed fatal and nonfatal cardiovascular events were shown to provide some evidence to suggest that statins might reduce cardiovascular events despite the low risk category and the relatively low levels of cholesterol. The magnitude of this beneficial
la re cente e tude Un cardiologue et un pneumologue ont examine neutre STATCOPE (Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations) au sujet des duction du risque cardiovasculaire par les questions relatives à la re iotropiques statines. Bien que les avantages potentiels des effets ple te condes statines contre cette maladie inflammatoire n’aient pas e s, l’effet à long terme contre la morbidite respiratoire et carfirme . La pre sente e tude e tait unique diovasculaire totale demeure inexplore tude sur les statines à puisque jusqu’à maintenant elle est la seule e utiliser des lignes directrices nationales (Adult Treatment Panel III) pour exclure les patients de l’essai s’ils ont un risque cardiovasculaire te suffisant pour justifier le traitement par les statines. De plus, il a e montre que les e ve nements cardiovasculaires fatals et non fatals de s fournissent des preuves selon lesquelles les statines observe
The Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) was a multicentre trial based on the hypothesis that pleiotropism of statins might reduce exacerbation rates or improve time to first exacerbations in patients with chronic obstructive lung disease (COLD) or chronic obstructive pulmonary disease (COPD).1 A previous observational study suggested that COPD exacerbations could be reduced with statins.2 Eight hundred eighty-five patients aged 40-80 years, with a ratio of forced expiratory volume in 1 second to forced vital capacity ratio < 70% and a forced expiratory volume in 1 second < 80% predicted after bronchodilator use were randomized to placebo or simvastatin 40 mg. Participants were former or current smokers with lifetime consumption of 10 or more pack-years and with at least 1 of the following within the previous year: use of supplemental oxygen, systemic glucocorticoids or antibiotic agents for respiratory problems;
presentation to the emergency department or hospitalization for COPD exacerbations. The trial was stopped due to futility. What lessons and residual questions emerge from this landmark trial regarding optimal management of COPD?
Received for publication February 13, 2015. Accepted March 11, 2015. Corresponding author: Dr G.B. John Mancini, Vancouver Hospital Research Pavilion Room 486, 828 West 10th Ave, Vancouver, British Columbia V7W 1L8, Canada. Tel.: þ1-604-875-5477; fax: þ1-604-8755471. E-mail: [email protected] See page 972 for disclosure information.
Disease-Modifying/Pleiotropic Effects of Statins The hypothesis was based on much retrospective data showing benefits of statins surmised to be especially related to anti-inflammatory effects.3,4 The study design was well tailored to demonstrate such effects at least as manifested by exacerbations within a short time frame (mean follow-up time of < 2 years). More subtle effects on markers of inflammation that might impart benefit over a longer term have not yet been reported but importantly, beneficial effects on spirometry or respiratory-specific quality of life parameters were absent. Thus, in patients who had no guideline indication for statins, pleiotropic effects on lung-specific processes underlying exacerbations within the short-term were absent. It must be emphasized, however, that the broader dilemma facing patients with COPD is that cardiovascular (CV) events constitute another major reason for the intense interest in statins in COPD. In one of the largest COPD studies,5 27% of the mortality was attributed to CV events compared with 35% due to respiratory events. The STATCOPE trial must not be interpreted to indicate a neutral or negative result in
http://dx.doi.org/10.1016/j.cjca.2015.03.016 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Mancini and Road The STATCOPE Trial
971
trend paralleled the magnitude of lowering of low-density lipoprotein cholesterol achieved in the active statin arm. Finally, the authors questioned whether the current standard of care adequately includes adherence to any national lipid guideline or adequate attention to the cardiovascular comorbidity of these patients. In conclusion, knowledge translation of the STATCOPE trial should at a minimum encourage assessment of cardiovascular risk in patients with chronic obstructive pulmonary disease, implementation of proven cardiovascular risk reduction therapies based on national guidelines, including statins, and plans to undertake a trial adequate in size and duration to address cardiovascular event reduction in patients not already eligible for evidence-based risk-reducing therapies.
duiraient les e ve nements cardiovasculaires en de pit de la cate gorie re à faible risque et des concentrations relativement faibles de cholesrol. L’importance de cette tendance be ne fique coïncide avec l’imte rol à lipoprote ines de faible portance de la diminution du choleste atteinte dans le bras actif sur les statines. Finalement, les densite auteurs se demandent si la norme actuelle de soins comprend bien l’observance de toute recommandation nationale sur les lipides ou cessaire concernant la comorbidite cardiovasculaire de l’attention ne ces patients. En conclusion, la transmission des connaissances sur tude STATCOPE devrait au moins encourager l’e valuation du risque l’e cardiovasculaire chez les patients souffrant de bronchopneumopathie prouve s chronique obstructive, la mise en place de traitements e duction du risque cardiovasculaire fonde s sur les lignes favorisant la re directrices nationales, y compris les statines, et de plans pour entre en taille et en dure e pour re duire les prendre un essai approprie ve nements cardiovasculaires chez les patients qui ne sont pas de jà e duction du risque fonde s admissibles aux traitements favorisant la re es probantes. sur des donne
this broader scope of potential benefit because the investigators assiduously avoided initial enrollment of patients already receiving or warranting statin treatment (based on Adult Treatment Panel [ATP] III risk stratification)6 and subsequently also discontinued study drug in patients receiving CV drugs such as amlodipine or high doses of verapamil and additionally ultimately excluded patients with diabetes or a glycated hemoglobin level of > 6.5%.1 These decisions, in concert with an average low-density lipoprotein cholesterol (LDL-C) level just < 3.0 mmol/L, effectively identified a cohort with extremely low risk of CV events, verified by the observed, low rate of CV events. This observation in turn, however, is somewhat provocative and serves to fuel ongoing debates that are not prominent within respiratory medicine but are raging within the lipid and CV communities.
randomized controlled trial to at least identify patients who would not benefit from use of a statin?
Use of a Guideline to Identify Patients Eligible for a Statin Trial Although STATCOPE was not a CV outcome study, it is the only statin trial that has used a national guideline to influence patient selection.6 The absence of any such trial to date has been a rallying cry for those who denigrate the validity of guidelines and algorithms for selection of patients who warrant therapy. Thus, results of STATCOPE suggest that ATP III can be used to identify a population that does not warrant statin therapy, even in the presence of the “nontraditional” CV risk imparted by COPD. This is very alarming in consideration of the demographic characteristics of the STATCOPE population. They were mainly men, with an average age of 62 years, with 50 pack-years of smoking, and at least a 30% current smoking rate. Using either the new Pooled Cohort Equations in the United States7 or the Canadian Cardiovascular Society application of the Framingham risk stratification8, a male smoker at this age with no other risk factors and with an LDL-C just < 3.0 mmol/L would warrant statin therapy, would have been excluded in Canada and now also in the United States. So are kudos warranted for ATP III? Have we thrown out a guideline that has now been shown in a
Does STATCOPE Refute the Observation That Statins Lower CV Risk, Irrespective of Estimated CV Risk? The CV outcomes in STATCOPE were infrequent. Fatal events were reported as percentage of patients and nonfatal events were reported as events per person-years. Table 1 shows events on a per patient-year of follow-up using the reported events and the disclosed mean days of follow-up in the 2 groups.1 Simple aggregation from the published results might overestimate events if nonfatal events occurred before fatal events and were “double counted.” This serves to underscore that the ATP III screening approach truly identified patients at low CV risk. This aggregation of fatal and nonfatal CV events, even if overestimated, still yielded low rates but with a trend favouring the statin-treated arm by 20%. Although this 20% reduction must be viewed with caution, it is nevertheless not out of line with what is expected of statin therapy. Absence of statistical significance with this degree of reduction and at such low event rates suggests low power. It would be erroneous to interpret STATCOPE as having excluded a role for statins even in these low risk COPD patients. Although this might appear fanciful, it is worth considering 2 other trials that were predicated on the possible benefit of Table 1. Total fatal and nonfatal CVEs Events (per patient-year) Nonfatal CVE Other nonfatal CVE Total nonfatal CVE Fatal heart event Other fatal CVE Total fatal CVE Total fatal and nonfatal CVE CVEs, cardiovascular events. Data from Criner et al.1
Statin-treated (n ¼ 430)
Placebo-treated (n ¼ 447)
0.04 0.03 0.07 0.00 0.0053 0.0053 0.08
0.01 0.08 0.09 0.0013 0.0038 0.0051 0.10
972
statins in the presence of “nontraditional” risk markers, namely, the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial9 and the SHARP trial.10 The JUPITER trial examined the effects of statins in patients with LDL-C levels below thresholds for therapy at the time (< 3.5 mmol/L) but who had the additional risk marker of increased levels of highsensitivity C-reactive protein (hs-CRP). The Study Heart and Renal Protection (SHARP) trial did not use a lipid criterion for eligibility but identified patients on the basis of abnormal renal function (mainly estimated glomerular filtration rate < 60 mL/min), with most pre-dialysis-dependent. Both trials were adequately powered to identify CV benefits. In JUPITER, hs-CRP-lowering was shown to be associated with CV risk reduction but this is being studied further using antiinflammatory agents not confounded by benefit of lipidlowering per se. In SHARP, although renal function was not improved, CV events were lowered in parallel with lipidlowering. Furthermore, the approximated observed rates of events shown in Table 1 suggest that over 2 years one might anticipate CV events in 16% of the statin-treated group and in 20% of the placebo-treated group. This absolute risk reduction of 4% yielded a number needed to treat of only 25 over 2 years. This is actually lower than the 2-year number needed to treat reported for the JUPITER trial, possibly related to our simplistic aggregation of reported events. Nevertheless, this underscores that the CV benefit of statins should not be discounted on the basis of STATCOPE. Does STATCOPE Refute the Observation That CV Risk Reduction Is Independent of LDL-C? The LDL-C levels averaged only 2.95 mmol/L and decreased by 0.9 mmol/L to 2.1 in the statin-treated group. In the placebo-treated group the comparable values were 2.96, 0.17, and 2.7 mmol/L, respectively; a 22% difference and a 29% decrease in LDL-C in the statin-treated group. Thus, extent of lowering of LDL-C in this nondyslipidemic population is concordant in direction and magnitude with the estimated CV event reduction trend noted herein. Are Statin-Eligible Patients With COPD Actually Getting Statins? CV risk reduction in COPD is known to be underused.11 There were 1217 patients screened and 332 were excluded. We do not know the extent to which COPD patients already receiving statins were not approached and so the sample might not be typical of the broad spectrum of COPD patients. However, of those screened, 7 had diabetes (not known if receiving statins but presumably not), 11 were receiving statins, 38 should have been receiving them based on ATP III, and 5 were unable to take statins but presumably were eligible on some basis before screening. Accordingly, this subgroup of excluded patients totals at least 46 and possibly up to 51 who should have been receiving statins and yet only 11 (22%-24%) were receiving them. Had current US or Canadian guidelines been used to identify statin-eligible patients, the proportion of statin-eligible COPD patients would likely have been greater and the
Canadian Journal of Cardiology Volume 31 2015
proportion not taking them might also have been higher. Moreover, although COPD guidelines emphasize attention to comorbidities, there is nothing explicit about CV risk assessment or use of statins when indicated. Conclusions STATCOPE must not detract from the need to improve total morbidity and mortality over the long-term in COPD. Although the now superseded ATP III approach successfully identified patients at low CV risk, we suggest that even this population might well have gained a significant benefit from statin use. At a minimum, the STATCOPE study design overtly conceded that CV risk assessment should be used to identify those who warrant statin treatment. So, are statins out in the COLD? Yes, but they should not be for those who meet guidelines for statin use. For the remainder, a trial adequately powered to assess CV benefit, and with additional focus on COPD end points over the longer-term is still warranted. Disclosure G.B.J.M. discloses honoraria from Amgen, Sanofi-Aventis, and Regeneron; J.R. has no conflicts of interest to disclose. References 1. Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014;370: 2201-10. 2. Blamoun AI, Batty GN, DeBari VA, et al. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract 2008;62: 1373-8. 3. Mancini GB, Etminan M, Zhang B, et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47:2554-60. 4. Horita N, Miyazawa N, Kojima R, et al. Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and metaanalysis of observational studies. Respir Res 2014;15:80. 5. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89. 6. National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Final Report. Available at: http://www.nhlbi.nih. gov/files/docs/resources/heart/atp3full.pdf. Accessed February 13, 2015. 7. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 suppl 2):S1-45. 8. Anderson TJ, Gregoire J, Hegele RA, et al. 2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol 2013;29:151-67.
Mancini and Road The STATCOPE Trial 9. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207. 10. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal
973
Protection): a randomised 2011;377:2181-92.
placebo-controlled
trial.
Lancet
11. Du Q, Sun Y, Ding N, Lu L, Chen Y. Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a meta-analysis of observational studies. PLoS One 2014;9:e113048.
Viewpoint
Are Statins out in the COLD? The STATCOPE Trial G.B. John Mancini, MD, FRCPC,a and Jeremy Road, MD, FRCPCb a
Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
b
Respiratory Medicine, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
ABSTRACT
RESUM E
A cardiologist and respirologist examined the recent, neutral Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) for issues of relevance to cardiovascular risk reduction with statin medications. Although the potential benefit of the pleiotropic effects of statins on this inflammatory disease was not borne out, the effect over the longer term on total respiratory and cardiovascular morbidity and mortality remain unexplored. This study was unique as the only statin trial to date to use a national guideline (Adult Treatment Panel III) to exclude patients from the trial if at sufficient cardiovascular risk to warrant statin therapy. Furthermore, observed fatal and nonfatal cardiovascular events were shown to provide some evidence to suggest that statins might reduce cardiovascular events despite the low risk category and the relatively low levels of cholesterol. The magnitude of this beneficial
la re cente e tude Un cardiologue et un pneumologue ont examine neutre STATCOPE (Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations) au sujet des duction du risque cardiovasculaire par les questions relatives à la re iotropiques statines. Bien que les avantages potentiels des effets ple te condes statines contre cette maladie inflammatoire n’aient pas e s, l’effet à long terme contre la morbidite respiratoire et carfirme . La pre sente e tude e tait unique diovasculaire totale demeure inexplore tude sur les statines à puisque jusqu’à maintenant elle est la seule e utiliser des lignes directrices nationales (Adult Treatment Panel III) pour exclure les patients de l’essai s’ils ont un risque cardiovasculaire te suffisant pour justifier le traitement par les statines. De plus, il a e montre que les e ve nements cardiovasculaires fatals et non fatals de s fournissent des preuves selon lesquelles les statines observe
The Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) was a multicentre trial based on the hypothesis that pleiotropism of statins might reduce exacerbation rates or improve time to first exacerbations in patients with chronic obstructive lung disease (COLD) or chronic obstructive pulmonary disease (COPD).1 A previous observational study suggested that COPD exacerbations could be reduced with statins.2 Eight hundred eighty-five patients aged 40-80 years, with a ratio of forced expiratory volume in 1 second to forced vital capacity ratio < 70% and a forced expiratory volume in 1 second < 80% predicted after bronchodilator use were randomized to placebo or simvastatin 40 mg. Participants were former or current smokers with lifetime consumption of 10 or more pack-years and with at least 1 of the following within the previous year: use of supplemental oxygen, systemic glucocorticoids or antibiotic agents for respiratory problems;
presentation to the emergency department or hospitalization for COPD exacerbations. The trial was stopped due to futility. What lessons and residual questions emerge from this landmark trial regarding optimal management of COPD?
Received for publication February 13, 2015. Accepted March 11, 2015. Corresponding author: Dr G.B. John Mancini, Vancouver Hospital Research Pavilion Room 486, 828 West 10th Ave, Vancouver, British Columbia V7W 1L8, Canada. Tel.: þ1-604-875-5477; fax: þ1-604-8755471. E-mail: [email protected] See page 972 for disclosure information.
Disease-Modifying/Pleiotropic Effects of Statins The hypothesis was based on much retrospective data showing benefits of statins surmised to be especially related to anti-inflammatory effects.3,4 The study design was well tailored to demonstrate such effects at least as manifested by exacerbations within a short time frame (mean follow-up time of < 2 years). More subtle effects on markers of inflammation that might impart benefit over a longer term have not yet been reported but importantly, beneficial effects on spirometry or respiratory-specific quality of life parameters were absent. Thus, in patients who had no guideline indication for statins, pleiotropic effects on lung-specific processes underlying exacerbations within the short-term were absent. It must be emphasized, however, that the broader dilemma facing patients with COPD is that cardiovascular (CV) events constitute another major reason for the intense interest in statins in COPD. In one of the largest COPD studies,5 27% of the mortality was attributed to CV events compared with 35% due to respiratory events. The STATCOPE trial must not be interpreted to indicate a neutral or negative result in
http://dx.doi.org/10.1016/j.cjca.2015.03.016 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Mancini and Road The STATCOPE Trial
971
trend paralleled the magnitude of lowering of low-density lipoprotein cholesterol achieved in the active statin arm. Finally, the authors questioned whether the current standard of care adequately includes adherence to any national lipid guideline or adequate attention to the cardiovascular comorbidity of these patients. In conclusion, knowledge translation of the STATCOPE trial should at a minimum encourage assessment of cardiovascular risk in patients with chronic obstructive pulmonary disease, implementation of proven cardiovascular risk reduction therapies based on national guidelines, including statins, and plans to undertake a trial adequate in size and duration to address cardiovascular event reduction in patients not already eligible for evidence-based risk-reducing therapies.
duiraient les e ve nements cardiovasculaires en de pit de la cate gorie re à faible risque et des concentrations relativement faibles de cholesrol. L’importance de cette tendance be ne fique coïncide avec l’imte rol à lipoprote ines de faible portance de la diminution du choleste atteinte dans le bras actif sur les statines. Finalement, les densite auteurs se demandent si la norme actuelle de soins comprend bien l’observance de toute recommandation nationale sur les lipides ou cessaire concernant la comorbidite cardiovasculaire de l’attention ne ces patients. En conclusion, la transmission des connaissances sur tude STATCOPE devrait au moins encourager l’e valuation du risque l’e cardiovasculaire chez les patients souffrant de bronchopneumopathie prouve s chronique obstructive, la mise en place de traitements e duction du risque cardiovasculaire fonde s sur les lignes favorisant la re directrices nationales, y compris les statines, et de plans pour entre en taille et en dure e pour re duire les prendre un essai approprie ve nements cardiovasculaires chez les patients qui ne sont pas de jà e duction du risque fonde s admissibles aux traitements favorisant la re es probantes. sur des donne
this broader scope of potential benefit because the investigators assiduously avoided initial enrollment of patients already receiving or warranting statin treatment (based on Adult Treatment Panel [ATP] III risk stratification)6 and subsequently also discontinued study drug in patients receiving CV drugs such as amlodipine or high doses of verapamil and additionally ultimately excluded patients with diabetes or a glycated hemoglobin level of > 6.5%.1 These decisions, in concert with an average low-density lipoprotein cholesterol (LDL-C) level just < 3.0 mmol/L, effectively identified a cohort with extremely low risk of CV events, verified by the observed, low rate of CV events. This observation in turn, however, is somewhat provocative and serves to fuel ongoing debates that are not prominent within respiratory medicine but are raging within the lipid and CV communities.
randomized controlled trial to at least identify patients who would not benefit from use of a statin?
Use of a Guideline to Identify Patients Eligible for a Statin Trial Although STATCOPE was not a CV outcome study, it is the only statin trial that has used a national guideline to influence patient selection.6 The absence of any such trial to date has been a rallying cry for those who denigrate the validity of guidelines and algorithms for selection of patients who warrant therapy. Thus, results of STATCOPE suggest that ATP III can be used to identify a population that does not warrant statin therapy, even in the presence of the “nontraditional” CV risk imparted by COPD. This is very alarming in consideration of the demographic characteristics of the STATCOPE population. They were mainly men, with an average age of 62 years, with 50 pack-years of smoking, and at least a 30% current smoking rate. Using either the new Pooled Cohort Equations in the United States7 or the Canadian Cardiovascular Society application of the Framingham risk stratification8, a male smoker at this age with no other risk factors and with an LDL-C just < 3.0 mmol/L would warrant statin therapy, would have been excluded in Canada and now also in the United States. So are kudos warranted for ATP III? Have we thrown out a guideline that has now been shown in a
Does STATCOPE Refute the Observation That Statins Lower CV Risk, Irrespective of Estimated CV Risk? The CV outcomes in STATCOPE were infrequent. Fatal events were reported as percentage of patients and nonfatal events were reported as events per person-years. Table 1 shows events on a per patient-year of follow-up using the reported events and the disclosed mean days of follow-up in the 2 groups.1 Simple aggregation from the published results might overestimate events if nonfatal events occurred before fatal events and were “double counted.” This serves to underscore that the ATP III screening approach truly identified patients at low CV risk. This aggregation of fatal and nonfatal CV events, even if overestimated, still yielded low rates but with a trend favouring the statin-treated arm by 20%. Although this 20% reduction must be viewed with caution, it is nevertheless not out of line with what is expected of statin therapy. Absence of statistical significance with this degree of reduction and at such low event rates suggests low power. It would be erroneous to interpret STATCOPE as having excluded a role for statins even in these low risk COPD patients. Although this might appear fanciful, it is worth considering 2 other trials that were predicated on the possible benefit of Table 1. Total fatal and nonfatal CVEs Events (per patient-year) Nonfatal CVE Other nonfatal CVE Total nonfatal CVE Fatal heart event Other fatal CVE Total fatal CVE Total fatal and nonfatal CVE CVEs, cardiovascular events. Data from Criner et al.1
Statin-treated (n ¼ 430)
Placebo-treated (n ¼ 447)
0.04 0.03 0.07 0.00 0.0053 0.0053 0.08
0.01 0.08 0.09 0.0013 0.0038 0.0051 0.10
972
statins in the presence of “nontraditional” risk markers, namely, the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial9 and the SHARP trial.10 The JUPITER trial examined the effects of statins in patients with LDL-C levels below thresholds for therapy at the time (< 3.5 mmol/L) but who had the additional risk marker of increased levels of highsensitivity C-reactive protein (hs-CRP). The Study Heart and Renal Protection (SHARP) trial did not use a lipid criterion for eligibility but identified patients on the basis of abnormal renal function (mainly estimated glomerular filtration rate < 60 mL/min), with most pre-dialysis-dependent. Both trials were adequately powered to identify CV benefits. In JUPITER, hs-CRP-lowering was shown to be associated with CV risk reduction but this is being studied further using antiinflammatory agents not confounded by benefit of lipidlowering per se. In SHARP, although renal function was not improved, CV events were lowered in parallel with lipidlowering. Furthermore, the approximated observed rates of events shown in Table 1 suggest that over 2 years one might anticipate CV events in 16% of the statin-treated group and in 20% of the placebo-treated group. This absolute risk reduction of 4% yielded a number needed to treat of only 25 over 2 years. This is actually lower than the 2-year number needed to treat reported for the JUPITER trial, possibly related to our simplistic aggregation of reported events. Nevertheless, this underscores that the CV benefit of statins should not be discounted on the basis of STATCOPE. Does STATCOPE Refute the Observation That CV Risk Reduction Is Independent of LDL-C? The LDL-C levels averaged only 2.95 mmol/L and decreased by 0.9 mmol/L to 2.1 in the statin-treated group. In the placebo-treated group the comparable values were 2.96, 0.17, and 2.7 mmol/L, respectively; a 22% difference and a 29% decrease in LDL-C in the statin-treated group. Thus, extent of lowering of LDL-C in this nondyslipidemic population is concordant in direction and magnitude with the estimated CV event reduction trend noted herein. Are Statin-Eligible Patients With COPD Actually Getting Statins? CV risk reduction in COPD is known to be underused.11 There were 1217 patients screened and 332 were excluded. We do not know the extent to which COPD patients already receiving statins were not approached and so the sample might not be typical of the broad spectrum of COPD patients. However, of those screened, 7 had diabetes (not known if receiving statins but presumably not), 11 were receiving statins, 38 should have been receiving them based on ATP III, and 5 were unable to take statins but presumably were eligible on some basis before screening. Accordingly, this subgroup of excluded patients totals at least 46 and possibly up to 51 who should have been receiving statins and yet only 11 (22%-24%) were receiving them. Had current US or Canadian guidelines been used to identify statin-eligible patients, the proportion of statin-eligible COPD patients would likely have been greater and the
Canadian Journal of Cardiology Volume 31 2015
proportion not taking them might also have been higher. Moreover, although COPD guidelines emphasize attention to comorbidities, there is nothing explicit about CV risk assessment or use of statins when indicated. Conclusions STATCOPE must not detract from the need to improve total morbidity and mortality over the long-term in COPD. Although the now superseded ATP III approach successfully identified patients at low CV risk, we suggest that even this population might well have gained a significant benefit from statin use. At a minimum, the STATCOPE study design overtly conceded that CV risk assessment should be used to identify those who warrant statin treatment. So, are statins out in the COLD? Yes, but they should not be for those who meet guidelines for statin use. For the remainder, a trial adequately powered to assess CV benefit, and with additional focus on COPD end points over the longer-term is still warranted. Disclosure G.B.J.M. discloses honoraria from Amgen, Sanofi-Aventis, and Regeneron; J.R. has no conflicts of interest to disclose. References 1. Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014;370: 2201-10. 2. Blamoun AI, Batty GN, DeBari VA, et al. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract 2008;62: 1373-8. 3. Mancini GB, Etminan M, Zhang B, et al. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47:2554-60. 4. Horita N, Miyazawa N, Kojima R, et al. Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and metaanalysis of observational studies. Respir Res 2014;15:80. 5. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89. 6. National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Final Report. Available at: http://www.nhlbi.nih. gov/files/docs/resources/heart/atp3full.pdf. Accessed February 13, 2015. 7. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 suppl 2):S1-45. 8. Anderson TJ, Gregoire J, Hegele RA, et al. 2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol 2013;29:151-67.
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