Letters
be considered a meaningful number.” However, random measurement error in cohort studies generally attenuates the association, which means that the association would be stronger if no or little measure error was present. Furthermore, Figure 1 in our article1 showed that increasing red meat intake within a 4-year period was positively associated with T2DM in the subsequent 4 years in a doseresponsive manner, not “the effect of reducing meat consumption, which increased the frequency of diabetes in all the cohorts studied,” as claimed by Dr Feinman. Dr Feinman also stated, “In fact, red meat consumption decreased as T2DM increased during the past 30 years.” However, this ecological relationship cannot be used to argue against the causal relationship between red meat intake and T2DM because many other factors have changed over time. Components in red meat that may contribute to T2DM risk include heme iron, high saturated fat and cholesterol, added sodium and nitrites and nitrates in processed meat, and potential mechanisms include increased weight gain, inflammation and advanced glycation end products.5 On the basis of the criteria by Hill,2 we have shown a temporal relation, a relatively strong association, consistency with previous publications, a doseresponse relationship, and a relation with strong biological plausibility. Therefore, there is compelling evidence that increasing red meat intake is causally related to risk of T2DM. An Pan, PhD Frank B. Hu, MD, PhD Author Affiliations: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts (Pan, Hu); Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (Hu); Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Hu); Saw Swee Hock School of Public Health and Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (Pan). Corresponding Author: An Pan, PhD, Saw Swee Hock School of Public Health, National University of Singapore, 16 Medical Dr, Singapore 117597 (ephanp@nus .edu.sg). Conflict of Interest Disclosures: None reported. 1. Pan A, Sun Q, Bernstein AM, Manson JE, Willett WC, Hu FB. Changes in red meat consumption and subsequent risk of type 2 diabetes mellitus: three cohorts of US men and women. JAMA Intern Med. 2013;173(14):1328-1335. 2. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295-300. 3. Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2007;298(22):2654-2664. 4. Jeon CY, Lokken RP, Hu FB, van Dam RM. Physical activity of moderate intensity and risk of type 2 diabetes: a systematic review. Diabetes Care. 2007;30(3):744-752. 5. Pan A, Sun Q, Bernstein AM, et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. Am J Clin Nutr. 2011;94(4):1088-1096.
Bronchodilator Safety in Chronic Obstructive Pulmonary Disease: Time to Focus? To the Editor Chronic obstructive pulmonary disease (COPD) is a devastating disease with a high impact on patients’ wellbeing and on health care systems. As put forward by Woodruff,1 bronchodilators are an important and effective pharmajamainternalmedicine.com
ceutical treatment in many patients, whereas their effect on disease progression and mortality is minimal and debatable. While the debate on their safety profiles appeared settled for the COPD population at large, the study by Gershon et al1 again questions the (cardiovascular) safety of the long-acting varieties in elderly patients; their results revealed an association between newly prescribed long-acting bronchodilators and the risk to develop cardiovascular disease. However, it would be inequitable to base the prescription of these medications solely on results from hypothesis-generating study methods.2 Although their nested case-control study was thoroughly performed, including sophisticated attempts to control for (hidden) confounders, methodological issues related with the design remain of concern: performance of spirometry did not influence their study results, but the main concern is the lack of the resulting spirometry data itself. While the effect of the surrogate (mis)diagnosis of COPD and the severity of the disease have been countered to some extent, considerable adjustments were not possible. Moreover, misdiagnosis would be more likely because the association was found in the first weeks after prescription of the medication. Furthermore, as the severity of COPD, defined by the level of airflow limitation, is associated with both the prescription of long-acting bronchodilators and the risk to develop cardiovascular disease, spirometry data are necessary to conclude on the causality of the hazardous association revealed by Gershon et al.1,3,4 Although Gershon et al1 studied a “real-world” population, therefore allowing for important subgroups that are usually excluded, we suggest that appropriate studies should now be focused at these specific subgroups at risk, eg, those that continue smoking, those with coexisting cardiovascular disease, and/or those with asthmatic features. On the basis of conflicting studies and meta-analyses on safety profiles, we believe that in daily practice the pharmacologic treatment of COPD should currently be primarily directed by its effect on individual symptoms and well-being, with some caution in the specific subgroups at risk. Wouter D. van Dijk, MD, PhD Sabine C. Käyser, MD Author Affiliations: Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. (van Dijk, Käyser). Corresponding Author: Wouter D. van Dijk, MD, PhD, Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, PO Box 9101, Internal Postal Code 117, 6500 HB, Nijmegen, the Netherlands (w.vandijk @aios.umcn.nl). Conflict of Interest Disclosures: None reported. 1. Gershon A, Croxford R, Calzavara A, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med. 2013;173(13):1175-1185. 2. Rabe KF. Drug safety in COPD revisited: what is the number needed to analyze? Chest. 2012;142(2):271-274. 3. Schermer T, Heijdra Y, Zadel S, et al. Flow and volume responses after routine salbutamol reversibility testing in mild to very severe COPD. Respir Med. 2007;101(6):1355-1362. 4. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32(4):962-969. 5. Woodruff PG. Double-edged sword? JAMA Intern Med. 2013;173(13):1184-1185. JAMA Internal Medicine April 2014 Volume 174, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Simon Fraser University User on 06/05/2015
647
Letters
In Reply We thank Drs van Dijk and Käyser for their thoughtful comments on our study. They argue that our study design may be prone to residual confounding, despite our use of sophisticated methods to control for this. We agree and said so in our article.1 However, randomized trials are also prone to methodological limitations, particularly when attempting to assess harms of therapy, which observational studies can overcome. Specifically, randomized trials often exclude participants with comorbidities or demographic characteristics that would place them at increased risk of adverse events, even when such characteristics are common among patients who in clinical practice will go on to receive the treatments being evaluated. Also, as serious adverse events are typically infrequent and often unexpected, randomized trials commonly lack sufficient power to identify them adequately. Spirometry-measured airflow limitation is the not the only predictor of chronic obstructive pulmonary disease (COPD) severity, nor the best predictor.2 Previous exacerbations, which our study did capture, are the single best predictor of future exacerbations, a key determinant of disease severity.2,3 Nevertheless, as we stated in our article,1 our lack of access to spirometry results and other clinical details could have resulted in misdiagnosis or misclassification of disease severity. Consequently, our comparisons of use vs no use of a long-acting bronchodilator may have overstated cardiovascular risks owing to residual confounding by severity. However, this is likely much less relevant to comparisons between the 2 bronchodilator classes—the primary focus of our study—because they have essentially identical indications for use across the spectrum of COPD severity.2 Moreover, we demonstrated in our article that only under scenarios of extreme differential misclassification would our conclusions be altered. Randomized clinical trial evidence directly comparing long-acting β-agonists and long-acting anticholinergic bronchodilators in COPD is dominated overwhelmingly by a single study of 7376 patients, the Prevention of Exacerbations With Tiotropium in COPD (POET-COPD) trial, which found no significant difference between tiotropium and salmeterol in serious adverse cardiac events (rate ratio, 1.12; 95% CI, 0.84-1.50).4 More recently, a mixed treatment comparison meta-analysis found no significant difference in cardiovascular death between patients with COPD receiving tiotropium (in the same 18-μg HandiHaler [Boehringer Ingelheim Inc] formulation that we studied) compared with either a long-acting β-agonist (odds ratio, 1.27; 95% CI, 0.88-1.87) or a long-acting β-agonist combined with an inhaled corticosteroid (odds ratio, 1.17; 95% CI, 0.81-1.69).5 Our more precise estimates, derived from a population-based cohort of 53 256 patients, thereby confirm and extend the findings of existing randomized trials. We agree that choice of therapy in COPD should be based on considerations of benefit vs risk. We would add that such decisions need to be informed by all the evidence available. We believe that our study1 provides the best and most comprehensive current evidence to guide practice in this regard. On this basis, we recommend that concerns about cardiovascular risk should inform the decision to add a long-acting bronchodilator in the management of patients 648
with COPD, but should not be considered relevant to the choice between long-acting β-agonists and long-acting anticholinergics. Matthew B. Stanbrook, MD, PhD Michael Campitelli, MPH Andrea Gershon, MD, MSc Author Affiliations: Division of Respirology, Department of Medicine, University Health Network, Toronto, Ontario, Canada (Stanbrook); Division of Respirology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Gershon); Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (Stanbrook, Campitelli, Gershon); Division of Respirology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada (Stanbrook, Gershon); Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada (Stanbrook, Gershon). Corresponding Author: Andrea Gershon, MD, MSc, Institute for Clinical Evaluative Sciences, 2075 Bayview Ave, Ste G1 06, Toronto, ON M4N 3M5, Canada ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gershon A, Croxford R, Calzavara A, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med. 2013;173(13):1175-1185. 2. Global Strategy for the Diagnosis. Management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2013. http://www.goldcopd.org. Accessed October 17, 2013. 3. Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138. 4. Vogelmeier C, Hederer B, Glaab T, et al; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103. 5. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48-56.
Role of Nicotinic Acid in Atherosclerosis Prevention To the Editor Jackevicius et al1 recently published concerns that nicotinic acid use in the United States, especially extended-release niacin (Niaspan; AbbVie Inc), exceeds almost 6-fold of that in Canada. Their economic comparison and implied excess use was stimulated by the AIM-HIGH (the Atherothrombosis Intervention in Metabolic syndrome with low HDL [high-density lipoprotein]/high triglycerides: Impact on Global Health outcomes) and HPS-2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) studies. The AIM-HIGH study reported that in patients with atherosclerotic cardiovascular disease (CVD) already treated with a statin to a low-density lipoprotein cholesterol (LDL-C) level of 71 mg/dL (to convert to millimoles per liter, multiply by 0.0259), no incremental benefit occurred with the addition of nicotinic acid to a statin therapy over 36 months. In HPS-2 THRIVE (starting LDL-C level of 63 mg/dL), nicotinic acid, combined with the antiflushing agent laropiprant, did not decrease CVD risk further in the presence of statin therapy. 1 Both studies involved patients with proven CVD receiving statin therapy and essentially at the LDL-C target for high–CVD risk patients (
be considered a meaningful number.” However, random measurement error in cohort studies generally attenuates the association, which means that the association would be stronger if no or little measure error was present. Furthermore, Figure 1 in our article1 showed that increasing red meat intake within a 4-year period was positively associated with T2DM in the subsequent 4 years in a doseresponsive manner, not “the effect of reducing meat consumption, which increased the frequency of diabetes in all the cohorts studied,” as claimed by Dr Feinman. Dr Feinman also stated, “In fact, red meat consumption decreased as T2DM increased during the past 30 years.” However, this ecological relationship cannot be used to argue against the causal relationship between red meat intake and T2DM because many other factors have changed over time. Components in red meat that may contribute to T2DM risk include heme iron, high saturated fat and cholesterol, added sodium and nitrites and nitrates in processed meat, and potential mechanisms include increased weight gain, inflammation and advanced glycation end products.5 On the basis of the criteria by Hill,2 we have shown a temporal relation, a relatively strong association, consistency with previous publications, a doseresponse relationship, and a relation with strong biological plausibility. Therefore, there is compelling evidence that increasing red meat intake is causally related to risk of T2DM. An Pan, PhD Frank B. Hu, MD, PhD Author Affiliations: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts (Pan, Hu); Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (Hu); Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Hu); Saw Swee Hock School of Public Health and Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore (Pan). Corresponding Author: An Pan, PhD, Saw Swee Hock School of Public Health, National University of Singapore, 16 Medical Dr, Singapore 117597 (ephanp@nus .edu.sg). Conflict of Interest Disclosures: None reported. 1. Pan A, Sun Q, Bernstein AM, Manson JE, Willett WC, Hu FB. Changes in red meat consumption and subsequent risk of type 2 diabetes mellitus: three cohorts of US men and women. JAMA Intern Med. 2013;173(14):1328-1335. 2. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295-300. 3. Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2007;298(22):2654-2664. 4. Jeon CY, Lokken RP, Hu FB, van Dam RM. Physical activity of moderate intensity and risk of type 2 diabetes: a systematic review. Diabetes Care. 2007;30(3):744-752. 5. Pan A, Sun Q, Bernstein AM, et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. Am J Clin Nutr. 2011;94(4):1088-1096.
Bronchodilator Safety in Chronic Obstructive Pulmonary Disease: Time to Focus? To the Editor Chronic obstructive pulmonary disease (COPD) is a devastating disease with a high impact on patients’ wellbeing and on health care systems. As put forward by Woodruff,1 bronchodilators are an important and effective pharmajamainternalmedicine.com
ceutical treatment in many patients, whereas their effect on disease progression and mortality is minimal and debatable. While the debate on their safety profiles appeared settled for the COPD population at large, the study by Gershon et al1 again questions the (cardiovascular) safety of the long-acting varieties in elderly patients; their results revealed an association between newly prescribed long-acting bronchodilators and the risk to develop cardiovascular disease. However, it would be inequitable to base the prescription of these medications solely on results from hypothesis-generating study methods.2 Although their nested case-control study was thoroughly performed, including sophisticated attempts to control for (hidden) confounders, methodological issues related with the design remain of concern: performance of spirometry did not influence their study results, but the main concern is the lack of the resulting spirometry data itself. While the effect of the surrogate (mis)diagnosis of COPD and the severity of the disease have been countered to some extent, considerable adjustments were not possible. Moreover, misdiagnosis would be more likely because the association was found in the first weeks after prescription of the medication. Furthermore, as the severity of COPD, defined by the level of airflow limitation, is associated with both the prescription of long-acting bronchodilators and the risk to develop cardiovascular disease, spirometry data are necessary to conclude on the causality of the hazardous association revealed by Gershon et al.1,3,4 Although Gershon et al1 studied a “real-world” population, therefore allowing for important subgroups that are usually excluded, we suggest that appropriate studies should now be focused at these specific subgroups at risk, eg, those that continue smoking, those with coexisting cardiovascular disease, and/or those with asthmatic features. On the basis of conflicting studies and meta-analyses on safety profiles, we believe that in daily practice the pharmacologic treatment of COPD should currently be primarily directed by its effect on individual symptoms and well-being, with some caution in the specific subgroups at risk. Wouter D. van Dijk, MD, PhD Sabine C. Käyser, MD Author Affiliations: Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. (van Dijk, Käyser). Corresponding Author: Wouter D. van Dijk, MD, PhD, Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, PO Box 9101, Internal Postal Code 117, 6500 HB, Nijmegen, the Netherlands (w.vandijk @aios.umcn.nl). Conflict of Interest Disclosures: None reported. 1. Gershon A, Croxford R, Calzavara A, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med. 2013;173(13):1175-1185. 2. Rabe KF. Drug safety in COPD revisited: what is the number needed to analyze? Chest. 2012;142(2):271-274. 3. Schermer T, Heijdra Y, Zadel S, et al. Flow and volume responses after routine salbutamol reversibility testing in mild to very severe COPD. Respir Med. 2007;101(6):1355-1362. 4. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32(4):962-969. 5. Woodruff PG. Double-edged sword? JAMA Intern Med. 2013;173(13):1184-1185. JAMA Internal Medicine April 2014 Volume 174, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Simon Fraser University User on 06/05/2015
647
Letters
In Reply We thank Drs van Dijk and Käyser for their thoughtful comments on our study. They argue that our study design may be prone to residual confounding, despite our use of sophisticated methods to control for this. We agree and said so in our article.1 However, randomized trials are also prone to methodological limitations, particularly when attempting to assess harms of therapy, which observational studies can overcome. Specifically, randomized trials often exclude participants with comorbidities or demographic characteristics that would place them at increased risk of adverse events, even when such characteristics are common among patients who in clinical practice will go on to receive the treatments being evaluated. Also, as serious adverse events are typically infrequent and often unexpected, randomized trials commonly lack sufficient power to identify them adequately. Spirometry-measured airflow limitation is the not the only predictor of chronic obstructive pulmonary disease (COPD) severity, nor the best predictor.2 Previous exacerbations, which our study did capture, are the single best predictor of future exacerbations, a key determinant of disease severity.2,3 Nevertheless, as we stated in our article,1 our lack of access to spirometry results and other clinical details could have resulted in misdiagnosis or misclassification of disease severity. Consequently, our comparisons of use vs no use of a long-acting bronchodilator may have overstated cardiovascular risks owing to residual confounding by severity. However, this is likely much less relevant to comparisons between the 2 bronchodilator classes—the primary focus of our study—because they have essentially identical indications for use across the spectrum of COPD severity.2 Moreover, we demonstrated in our article that only under scenarios of extreme differential misclassification would our conclusions be altered. Randomized clinical trial evidence directly comparing long-acting β-agonists and long-acting anticholinergic bronchodilators in COPD is dominated overwhelmingly by a single study of 7376 patients, the Prevention of Exacerbations With Tiotropium in COPD (POET-COPD) trial, which found no significant difference between tiotropium and salmeterol in serious adverse cardiac events (rate ratio, 1.12; 95% CI, 0.84-1.50).4 More recently, a mixed treatment comparison meta-analysis found no significant difference in cardiovascular death between patients with COPD receiving tiotropium (in the same 18-μg HandiHaler [Boehringer Ingelheim Inc] formulation that we studied) compared with either a long-acting β-agonist (odds ratio, 1.27; 95% CI, 0.88-1.87) or a long-acting β-agonist combined with an inhaled corticosteroid (odds ratio, 1.17; 95% CI, 0.81-1.69).5 Our more precise estimates, derived from a population-based cohort of 53 256 patients, thereby confirm and extend the findings of existing randomized trials. We agree that choice of therapy in COPD should be based on considerations of benefit vs risk. We would add that such decisions need to be informed by all the evidence available. We believe that our study1 provides the best and most comprehensive current evidence to guide practice in this regard. On this basis, we recommend that concerns about cardiovascular risk should inform the decision to add a long-acting bronchodilator in the management of patients 648
with COPD, but should not be considered relevant to the choice between long-acting β-agonists and long-acting anticholinergics. Matthew B. Stanbrook, MD, PhD Michael Campitelli, MPH Andrea Gershon, MD, MSc Author Affiliations: Division of Respirology, Department of Medicine, University Health Network, Toronto, Ontario, Canada (Stanbrook); Division of Respirology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Gershon); Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (Stanbrook, Campitelli, Gershon); Division of Respirology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada (Stanbrook, Gershon); Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada (Stanbrook, Gershon). Corresponding Author: Andrea Gershon, MD, MSc, Institute for Clinical Evaluative Sciences, 2075 Bayview Ave, Ste G1 06, Toronto, ON M4N 3M5, Canada ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gershon A, Croxford R, Calzavara A, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med. 2013;173(13):1175-1185. 2. Global Strategy for the Diagnosis. Management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2013. http://www.goldcopd.org. Accessed October 17, 2013. 3. Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138. 4. Vogelmeier C, Hederer B, Glaab T, et al; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093-1103. 5. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48-56.
Role of Nicotinic Acid in Atherosclerosis Prevention To the Editor Jackevicius et al1 recently published concerns that nicotinic acid use in the United States, especially extended-release niacin (Niaspan; AbbVie Inc), exceeds almost 6-fold of that in Canada. Their economic comparison and implied excess use was stimulated by the AIM-HIGH (the Atherothrombosis Intervention in Metabolic syndrome with low HDL [high-density lipoprotein]/high triglycerides: Impact on Global Health outcomes) and HPS-2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) studies. The AIM-HIGH study reported that in patients with atherosclerotic cardiovascular disease (CVD) already treated with a statin to a low-density lipoprotein cholesterol (LDL-C) level of 71 mg/dL (to convert to millimoles per liter, multiply by 0.0259), no incremental benefit occurred with the addition of nicotinic acid to a statin therapy over 36 months. In HPS-2 THRIVE (starting LDL-C level of 63 mg/dL), nicotinic acid, combined with the antiflushing agent laropiprant, did not decrease CVD risk further in the presence of statin therapy. 1 Both studies involved patients with proven CVD receiving statin therapy and essentially at the LDL-C target for high–CVD risk patients (
