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Functional decline in peripheral arterial disease: Associations with the ankle-brachial index and leg symptoms
Preventive Cardiology
Effectiveness of Statin Therapy in Adults With Coronary Heart Disease
Abstracts
Wilt T, Bloomfield H, MacDonald R, et al. Arch Intern Med 2004; 164:1427–36.
Statin Therapy Improves Cardiovascular Outcome of Patients With Peripheral Artery Disease
Study Question: What is the optimal LDL-C goal in coronary heart disease (CHD) and what is the optimal level at which to initiate statin therapy? Methods: Randomized trials designed to evaluate statin therapy for the secondary prevention of CHD published between January 1966 and December 2002 were identified through MEDLINE and the Cochrane Library. Studies were included if they randomly assigned adults with CHD to statin therapy or control, enrolled at least 100 individuals per arm, and reported clinical outcomes and LDL-C levels. Results: A total of 69,511 individuals were included, of which 19 were in placebo-controlled trials. The mean age of patients was 63 years with a mean pretreatment LDL-C of 149 mg/dL; 23% were women. Statin therapy reduced CHD mortality or nonfatal myocardial infarction (MI) 25% (RR, 0.75; 95% CI, 0.71– 0.79), all-cause mortality 16% (RR, 0.84; 95% CI, 0.79 – 0.89) and CHD mortality 23% (RR, 0.77; 95% CI, 0.71– 0.83). Beneficial effects were seen in women and the elderly. There were no data to determine whether lowering the LDL-C level to less than 100 mg/dL was superior to lowering it to 100 –130 mg/dL. Statin therapy reduces mortality and morbidity in adults with CHD, even at pretreatment LDL-C levels as low as 100 mg/dL. Conclusions: Meta-regression analyses revealed risk reductions for CHD mortality or nonfatal MI and major vascular events across available pretreatment LDL-C levels. Perspective: The conclusions are similar to those recently recommended by the ACC/AHA panel regarding using statins in essentially all persons with CHD and other forms of atherosclerosis. The review did not include the most recent studies demonstrating “lower is better” (targeting LDL-C to ⬍70 mg/dL), particularly in the very high-risk cohorts such as CHD patients with diabetes, a recent acute coronary syndrome, or with other risk factors. MR
Schillinger M, Exner M, Mlekusch W, et al. Eur Heart J 2004;25: 742– 8. Study Question: What is the interrelationship among statin use, inflammation and outcome of high-risk patients with advanced atherosclerosis? Methods: Researchers prospectively studied 515 patients with severe peripheral artery disease (PAD) (median age 70 years, 296 males). The cardiovascular risk profile and laboratory parameters of inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid A [SAA], fibrinogen, serum albumin, neutrophil counts) were obtained, and patients were followed for a median of 21 months (interquartile range 12–25) for the occurrence of myocardial infarction (MI) and death. Results: Investigators observed 19 MIs (5 fatal and 14 nonfatal) and 65 deaths. Cumulative survival and eventfree survival rates (freedom from death and MI) at 6, 12 and 24 months were 97%, 95% and 89%, and 96%, 93% and 87%, respectively. Patients receiving statin therapy (n⫽269, 52%) had a lower level of inflammation (hs-CRP p⬍0.001, SAA p⫽0.001, fibrinogen p⫽0.007, albumin p⬍0.001, neutrophils p⫽0.049) and better survival (adjusted hazard ratio [HR] 0.52, p⫽0.022) and event-free survival rates (adjusted HR 0.48, p⫽0.004) than did patients not treated with statins. However, patients with low inflammatory activity (hs-CRP ⱕ0.42 mg/dL) had no significant benefit from statin therapy (p⫽0.74 for survival; p⫽0.83 for event-free survival), whereas in patients with high hs-CRP (⬎0.42 mg/dL) statin therapy was associated with a significantly reduced risk for mortality (adjusted HR 0.58, p⫽0.046) and the composite of MI and death (adjusted HR 0.46, p⫽0.016). Conclusions: The authors conclude that statin therapy is associated with a substantially improved intermediate-term survival of patients with severe PAD and a high inflammatory activity, whereas in patients with low hs-CRP no survival benefit was observed. Perspective: The study demonstrates that statin therapy is associated with substantially improved intermediate-term survival of patients with severe PAD and intense inflammatory activity; conversely, in patients with low hs-CRP no survival benefit was observed. It is appropriate to aggressively treat patients with PAD and high inflammatory activity with statins. Longer-term follow-up studies are needed to determine whether statins improve outcomes independent of LDL cholesterol and hs-CRP among patients with PAD. DM
Functional Decline in Peripheral Arterial Disease: Associations With the Ankle-Brachial Index and Leg Symptoms McDermott MM, Liu K, Greenland P, et al. JAMA 2004;292:453– 61. Study Question: Among individuals with lower-extremity peripheral arterial disease (PAD), specific leg symptoms and the ankle brachial index (ABI) are cross-sectionally related to the degree of functional impairment. However, relations between these clinical characteristics and objectively measured functional decline are unknown. The objective of this study was to define whether PAD, ABI, and specific leg symptoms predict functional decline at 2-year follow-up.
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Methods: This was a prospective cohort study among 676 consecutively identified individuals (aged ⬎55 years) with and without PAD (n⫽417 and n⫽259, respectively). PAD was defined as ABI ⬍0.90, and participants with PAD were categorized at baseline into 1 of 5 mutually exclusive symptom groups. The primary outcome measure was mean annual changes in 6-min walk performance and in usualpaced and fast-paced 4-m, walking velocity, adjusted for age, gender, race, prior-year functioning, comorbid diseases, body mass index, pack-years of cigarette smoking, and patterns of missing data. Results: Lower baseline ABI values were associated with greater mean (95% confidence interval) annual decline in 6-min walk performance (⫺73.0 [⫺142 to ⫺4.2] ft for ABI ⫺0.50 vs. ⫺58.8 [⫺83.5 to ⫺34.0] ft for ABI 0.50 to ⫺0.90 vs. ⫺12.6 [⫺40.3 to 15.1] ft for ABI 0.90 –1.50, p⫽0.02). Compared with participants without PAD, PAD subjects with leg pain on exertion and rest at baseline had greater mean annual decline in 6-min walk performance (⫺111 [⫺173 to ⫺50.0] ft vs. ⫺8.67 [⫺36.9 to 19.5] ft, p⫽0.004), usual-pace 4-m walking velocity (⫺0.06 [⫺0.09 to ⫺0.02] m/s vs. ⫺0.01 [⫺0.03 to 0.003] m/s, p⫽0.02), and fastest-pace 4-m walking velocity (⫺0.07 [⫺0.11 to ⫺0.03] m/s vs. ⫺0.02 [⫺0.04 to ⫺0.006] m/s, p⫽0.046). Compared with participants without PAD, asymptomatic PAD was associated with greater mean annual decline in 6-min walk performance (⫺76.8 [⫺135 to ⫺18.6] ft vs. ⫺8.67 [⫺36.9 to 19.5] ft, p⫽0.04) and an increased odds ratio for becoming unable to walk for 6 min continuously (3.63; 95% confidence interval, 1.58 – 8.36; p⫽0.002). Conclusions: The authors concluded that baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-year follow-up. Perspective: The study confirms the logical association between the presence and severity of PAD with significant decline in walking endurance over 2-year follow-up compared with individuals without PAD. The ABI values and leg symptoms can be used to identify patients with PAD who are at highest risk of functional decline. The findings underscore the importance of using ABI to identify persons with PAD in clinical practice, since PAD is frequently undiagnosed or asymptomatic. Further study is needed to develop treatments to prevent functional decline in PAD patients who do not have classic intermittent claudication. DM
clopidogrel alone in prevention of vascular events with potentially higher bleeding risk. Methods: Investigators performed a randomized, doubleblind, placebo-controlled trial to compare aspirin (75 mg/ day) with placebo in 7599 high-risk patients with recent ischemic stroke or transient ischemic attack and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day. Duration of treatment and follow-up was 18 months. The primary end point was a composite of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia (including rehospitalization for transient ischemic attack, angina pectoris, or worsening of peripheral arterial disease). Analysis was by intention to treat, using log-rank test and a Cox proportional-hazards model. Results: A total of 596 (15.7%) patients reached the primary end point in the group receiving aspirin and clopidogrel compared with 636 (16.7%) in the clopidogrel-alone group (relative risk reduction 6.4% [95% CI ⫺4.6 to 16.3]; absolute risk reduction 1% [⫺0.6 to 2.7]). Life-threatening bleedings were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (96 [2.6%] vs. 49 [1.3%]; absolute risk increase 1.3% [95% CI 0.6 to 1.9]). Major bleedings were also increased in the group receiving aspirin and clopidogrel, but no difference was recorded in mortality. Conclusions: The authors concluded that adding aspirin to clopidogrel in high-risk patients with recent ischemic stroke or transient ischemic attack is associated with a nonsignificant difference in reducing major vascular events. However, the risk of life-threatening or major bleeding is increased by the addition of aspirin. Perspective: Adding aspirin to clopidogrel in the MATCH trial resulted in a significantly higher bleeding rate that offset any beneficial effect, and the trial did not show additional clinical value of adding aspirin to clopidogrel in high-risk patients with transient ischemic attack or ischemic stroke. Additional information on the use of clopidogrel and aspirin combination therapy in patients at low risk of these events will be investigated in the CHARISMA trial comparing clopidogrel and aspirin with aspirin alone in primary and secondary prevention. Furthermore, data will also be forthcoming from several ongoing trials on patients with cerebrovascular disease of different causes. For now it appears prudent to avoid adding aspirin to clopidogrel for secondary stroke prevention. DM
Aspirin and Clopidogrel Compared With Clopidogrel Alone After Recent Ischemic Stroke or Transient Ischemic Attack in High-Risk Patients (MATCH): Randomized, Double-Blind, Placebo-Controlled Trial
Randomized Trials of Vitamin E in the Treatment and Prevention of Cardiovascular Disease
Diener HC, Bogousslavsky J, Brass LM, et al. on behalf of the MATCH Investigators. Lancet 2004;364:331–7.
Eidelman R, Hollar D, Herbert P, et al. Arch Intern Med 2004; 164:1552– 6.
Study Question: The investigators assessed whether addition of aspirin to clopidogrel could have a greater benefit than
Study Question: Is vitamin E effective in either the treatment or prevention of cardiovascular disease (CVD)?
ACC CURRENT JOURNAL REVIEW Oct 2004
17
Effectiveness of Statin Therapy in Adults With Coronary Heart Disease
Abstracts
Wilt T, Bloomfield H, MacDonald R, et al. Arch Intern Med 2004; 164:1427–36.
Statin Therapy Improves Cardiovascular Outcome of Patients With Peripheral Artery Disease
Study Question: What is the optimal LDL-C goal in coronary heart disease (CHD) and what is the optimal level at which to initiate statin therapy? Methods: Randomized trials designed to evaluate statin therapy for the secondary prevention of CHD published between January 1966 and December 2002 were identified through MEDLINE and the Cochrane Library. Studies were included if they randomly assigned adults with CHD to statin therapy or control, enrolled at least 100 individuals per arm, and reported clinical outcomes and LDL-C levels. Results: A total of 69,511 individuals were included, of which 19 were in placebo-controlled trials. The mean age of patients was 63 years with a mean pretreatment LDL-C of 149 mg/dL; 23% were women. Statin therapy reduced CHD mortality or nonfatal myocardial infarction (MI) 25% (RR, 0.75; 95% CI, 0.71– 0.79), all-cause mortality 16% (RR, 0.84; 95% CI, 0.79 – 0.89) and CHD mortality 23% (RR, 0.77; 95% CI, 0.71– 0.83). Beneficial effects were seen in women and the elderly. There were no data to determine whether lowering the LDL-C level to less than 100 mg/dL was superior to lowering it to 100 –130 mg/dL. Statin therapy reduces mortality and morbidity in adults with CHD, even at pretreatment LDL-C levels as low as 100 mg/dL. Conclusions: Meta-regression analyses revealed risk reductions for CHD mortality or nonfatal MI and major vascular events across available pretreatment LDL-C levels. Perspective: The conclusions are similar to those recently recommended by the ACC/AHA panel regarding using statins in essentially all persons with CHD and other forms of atherosclerosis. The review did not include the most recent studies demonstrating “lower is better” (targeting LDL-C to ⬍70 mg/dL), particularly in the very high-risk cohorts such as CHD patients with diabetes, a recent acute coronary syndrome, or with other risk factors. MR
Schillinger M, Exner M, Mlekusch W, et al. Eur Heart J 2004;25: 742– 8. Study Question: What is the interrelationship among statin use, inflammation and outcome of high-risk patients with advanced atherosclerosis? Methods: Researchers prospectively studied 515 patients with severe peripheral artery disease (PAD) (median age 70 years, 296 males). The cardiovascular risk profile and laboratory parameters of inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid A [SAA], fibrinogen, serum albumin, neutrophil counts) were obtained, and patients were followed for a median of 21 months (interquartile range 12–25) for the occurrence of myocardial infarction (MI) and death. Results: Investigators observed 19 MIs (5 fatal and 14 nonfatal) and 65 deaths. Cumulative survival and eventfree survival rates (freedom from death and MI) at 6, 12 and 24 months were 97%, 95% and 89%, and 96%, 93% and 87%, respectively. Patients receiving statin therapy (n⫽269, 52%) had a lower level of inflammation (hs-CRP p⬍0.001, SAA p⫽0.001, fibrinogen p⫽0.007, albumin p⬍0.001, neutrophils p⫽0.049) and better survival (adjusted hazard ratio [HR] 0.52, p⫽0.022) and event-free survival rates (adjusted HR 0.48, p⫽0.004) than did patients not treated with statins. However, patients with low inflammatory activity (hs-CRP ⱕ0.42 mg/dL) had no significant benefit from statin therapy (p⫽0.74 for survival; p⫽0.83 for event-free survival), whereas in patients with high hs-CRP (⬎0.42 mg/dL) statin therapy was associated with a significantly reduced risk for mortality (adjusted HR 0.58, p⫽0.046) and the composite of MI and death (adjusted HR 0.46, p⫽0.016). Conclusions: The authors conclude that statin therapy is associated with a substantially improved intermediate-term survival of patients with severe PAD and a high inflammatory activity, whereas in patients with low hs-CRP no survival benefit was observed. Perspective: The study demonstrates that statin therapy is associated with substantially improved intermediate-term survival of patients with severe PAD and intense inflammatory activity; conversely, in patients with low hs-CRP no survival benefit was observed. It is appropriate to aggressively treat patients with PAD and high inflammatory activity with statins. Longer-term follow-up studies are needed to determine whether statins improve outcomes independent of LDL cholesterol and hs-CRP among patients with PAD. DM
Functional Decline in Peripheral Arterial Disease: Associations With the Ankle-Brachial Index and Leg Symptoms McDermott MM, Liu K, Greenland P, et al. JAMA 2004;292:453– 61. Study Question: Among individuals with lower-extremity peripheral arterial disease (PAD), specific leg symptoms and the ankle brachial index (ABI) are cross-sectionally related to the degree of functional impairment. However, relations between these clinical characteristics and objectively measured functional decline are unknown. The objective of this study was to define whether PAD, ABI, and specific leg symptoms predict functional decline at 2-year follow-up.
ACC CURRENT JOURNAL REVIEW Oct 2004
16
Methods: This was a prospective cohort study among 676 consecutively identified individuals (aged ⬎55 years) with and without PAD (n⫽417 and n⫽259, respectively). PAD was defined as ABI ⬍0.90, and participants with PAD were categorized at baseline into 1 of 5 mutually exclusive symptom groups. The primary outcome measure was mean annual changes in 6-min walk performance and in usualpaced and fast-paced 4-m, walking velocity, adjusted for age, gender, race, prior-year functioning, comorbid diseases, body mass index, pack-years of cigarette smoking, and patterns of missing data. Results: Lower baseline ABI values were associated with greater mean (95% confidence interval) annual decline in 6-min walk performance (⫺73.0 [⫺142 to ⫺4.2] ft for ABI ⫺0.50 vs. ⫺58.8 [⫺83.5 to ⫺34.0] ft for ABI 0.50 to ⫺0.90 vs. ⫺12.6 [⫺40.3 to 15.1] ft for ABI 0.90 –1.50, p⫽0.02). Compared with participants without PAD, PAD subjects with leg pain on exertion and rest at baseline had greater mean annual decline in 6-min walk performance (⫺111 [⫺173 to ⫺50.0] ft vs. ⫺8.67 [⫺36.9 to 19.5] ft, p⫽0.004), usual-pace 4-m walking velocity (⫺0.06 [⫺0.09 to ⫺0.02] m/s vs. ⫺0.01 [⫺0.03 to 0.003] m/s, p⫽0.02), and fastest-pace 4-m walking velocity (⫺0.07 [⫺0.11 to ⫺0.03] m/s vs. ⫺0.02 [⫺0.04 to ⫺0.006] m/s, p⫽0.046). Compared with participants without PAD, asymptomatic PAD was associated with greater mean annual decline in 6-min walk performance (⫺76.8 [⫺135 to ⫺18.6] ft vs. ⫺8.67 [⫺36.9 to 19.5] ft, p⫽0.04) and an increased odds ratio for becoming unable to walk for 6 min continuously (3.63; 95% confidence interval, 1.58 – 8.36; p⫽0.002). Conclusions: The authors concluded that baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-year follow-up. Perspective: The study confirms the logical association between the presence and severity of PAD with significant decline in walking endurance over 2-year follow-up compared with individuals without PAD. The ABI values and leg symptoms can be used to identify patients with PAD who are at highest risk of functional decline. The findings underscore the importance of using ABI to identify persons with PAD in clinical practice, since PAD is frequently undiagnosed or asymptomatic. Further study is needed to develop treatments to prevent functional decline in PAD patients who do not have classic intermittent claudication. DM
clopidogrel alone in prevention of vascular events with potentially higher bleeding risk. Methods: Investigators performed a randomized, doubleblind, placebo-controlled trial to compare aspirin (75 mg/ day) with placebo in 7599 high-risk patients with recent ischemic stroke or transient ischemic attack and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day. Duration of treatment and follow-up was 18 months. The primary end point was a composite of ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia (including rehospitalization for transient ischemic attack, angina pectoris, or worsening of peripheral arterial disease). Analysis was by intention to treat, using log-rank test and a Cox proportional-hazards model. Results: A total of 596 (15.7%) patients reached the primary end point in the group receiving aspirin and clopidogrel compared with 636 (16.7%) in the clopidogrel-alone group (relative risk reduction 6.4% [95% CI ⫺4.6 to 16.3]; absolute risk reduction 1% [⫺0.6 to 2.7]). Life-threatening bleedings were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (96 [2.6%] vs. 49 [1.3%]; absolute risk increase 1.3% [95% CI 0.6 to 1.9]). Major bleedings were also increased in the group receiving aspirin and clopidogrel, but no difference was recorded in mortality. Conclusions: The authors concluded that adding aspirin to clopidogrel in high-risk patients with recent ischemic stroke or transient ischemic attack is associated with a nonsignificant difference in reducing major vascular events. However, the risk of life-threatening or major bleeding is increased by the addition of aspirin. Perspective: Adding aspirin to clopidogrel in the MATCH trial resulted in a significantly higher bleeding rate that offset any beneficial effect, and the trial did not show additional clinical value of adding aspirin to clopidogrel in high-risk patients with transient ischemic attack or ischemic stroke. Additional information on the use of clopidogrel and aspirin combination therapy in patients at low risk of these events will be investigated in the CHARISMA trial comparing clopidogrel and aspirin with aspirin alone in primary and secondary prevention. Furthermore, data will also be forthcoming from several ongoing trials on patients with cerebrovascular disease of different causes. For now it appears prudent to avoid adding aspirin to clopidogrel for secondary stroke prevention. DM
Aspirin and Clopidogrel Compared With Clopidogrel Alone After Recent Ischemic Stroke or Transient Ischemic Attack in High-Risk Patients (MATCH): Randomized, Double-Blind, Placebo-Controlled Trial
Randomized Trials of Vitamin E in the Treatment and Prevention of Cardiovascular Disease
Diener HC, Bogousslavsky J, Brass LM, et al. on behalf of the MATCH Investigators. Lancet 2004;364:331–7.
Eidelman R, Hollar D, Herbert P, et al. Arch Intern Med 2004; 164:1552– 6.
Study Question: The investigators assessed whether addition of aspirin to clopidogrel could have a greater benefit than
Study Question: Is vitamin E effective in either the treatment or prevention of cardiovascular disease (CVD)?
ACC CURRENT JOURNAL REVIEW Oct 2004
17