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Background: An internal thoracic artery graft to the left anterior descending artery is standard in coronary bypass surgery, but controversy exists on the best second conduit. The RAPCO trials (Radial Artery Patency and Clinical Outcomes) were designed to compare the long-term patency of the radial artery (RA) with that of the right internal thoracic artery (RITA) and the saphenous vein (SV). Methods: In RAPCO-RITA (the RITA versus RA arm of the RAPCO trial), 394 patients Results: In the RA versus RITA comparison, the estimated 10-year patency was 89% for RA versus 80% for free RITA (hazard ratio for graft failure, 0.45 [95% CI, 0.23–0.88]). Ten-year patient survival estimate was 90.9% in the RA arm versus 83.7% in the RITA arm (hazard ratio for mortality, 0.53 [95% CI, 0.30–0.95]). In the RA versus SV comparison, the estimated 10-year patency was 85% for the RA versus 71% for the SV (hazard ratio for graft failure, 0.40 [95% CI, 0.15–1.00]), and 10-year patient survival estimate was 72.6% for the RA group versus 65.2% for the SV group (hazard ratio for mortality, 0.76 [95% CI, 0.47–1.22]). Conclusions: The 10-year patency rate of the RA is significantly higher than that of the free RITA and better than that of the SV. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00475488.

Background: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events. Methods: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding. Results: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P =0.002; and hazard ratio, 0.77, P =0.005, respectively, P interaction =0.77) and all-cause mortality (hazard ratio, 0.81, P =0.05; and hazard ratio, 0.84, P =0.09, respectively; P interaction =0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative P interaction P interaction =0.02; 2.7% versus 1.7% for major vascular events, P interaction P interaction =0.001). Conclusions: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01776424.

Background: The neurocognitive effect of statins in older adults remains uncertain. Objectives: To investigate the associations of statin use with cognitive decline and incident dementia among older adults. Methods: This analysis included 18,846 participants (aged ≥65 years) from a randomized trial of aspirin (ASPirin in Reducing Events in the Elderly, ASPREE). At baseline, participants had no experience of a CVD event, major physical disability, or diagnosed dementia, and were followed for a median (IQR) of 4.7 (3.5-5.6) years. Outcome measures included incident dementia and its subclassifications (probable Alzheimer’s disease [AD]; mixed presentations), changes in domain-specific cognition (global cognition, memory, language and executive function, psychomotor speed) and the composite of these domains. We examined the associations of baseline statin use with dementia using Cox proportional-hazards models, and with cognitive change using linear mixed-effects models, adjusting for confounders. The role of statin lipophilicity was also examined. Results: Compared with no statin, baseline statin use was not associated with incident dementia (adjusted HR [95%CI]: 1.16 [0.97-1.40]), probable AD (1.33 [1.00-1.77]) or mixed presentations of dementia (1.06 [0.82-1.35]) ( Table 1 ). Nor was it associated with changes in composite or domain-specific cognitive function scores over time ( Table 2 ). No differences were found in any outcomes between hydrophilic and lipophilic statin users ( Tables 1 & 2 ). Conclusions: In healthy adults aged ≥65 years without diagnosed dementia, statin therapy over 4.7 years was not associated with incident dementia or cognitive decline.

Background: Strokes were significantly reduced by the combination of rivaroxaban plus aspirin in comparison with aspirin in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies). We present detailed analyses of stroke by type, predictors, and antithrombotic effects in key subgroups. Methods: Participants had stable coronary artery or peripheral artery disease and were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117), or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152). Patients who required anticoagulation or had a stroke within 1 month, previous lacunar stroke, or intracerebral hemorrhage were excluded. Results: During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 [0.9% per year] versus 142 [1.6% per year]; hazard ratio [HR], 0.58; 95% CI, 0.44–0.76; P P P =0.01). Independent predictors of stroke were prior stroke, hypertension, systolic blood pressure at baseline, age, diabetes mellitus, and Asian ethnicity. Prior stroke was the strongest predictor of incident stroke (HR, 3.63; 95% CI, 2.65–4.97; P Conclusions: Low-dose rivaroxaban plus aspirin is an important new antithrombotic option for primary and secondary stroke prevention in patients with clinical atherosclerosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.

Background Access to cardiac services is essential for appropriate implementation of evidence-based therapies to improve outcomes. The Cardiac Accessibility and Remoteness Index for Australia (Cardiac ARIA) aimed to derive an objective, geographic measure reflecting access to cardiac services. Methods and Results An expert panel defined an evidence-based clinical pathway. Using Geographic Information Systems (GIS), the team developed a numeric/alphabetic index at 2 points along the continuum of care. The acute category (numeric) measured the time from the emergency call to arrival at an appropriate medical facility via road ambulance. The aftercare category (alphabetic) measured access to 4 basic services (family doctor, pharmacy, cardiac rehabilitation, and pathology services) when a patient returned to his or her community. The numeric index ranged from 1 (access to principal referral center with cardiac catheterization service ≤1 hour) to 8 (no ambulance service, >3 hours to medical facility, air transport required). The alphabetic index ranged from A (all 4 services available within a 1-hour drive-time) to E (no services available within 1 hour). The panel found that 13.9 million Australians (71%) resided within Cardiac ARIA 1A locations (hospital with cardiac catheterization laboratory and all aftercare within 1 hour). Those outside Cardiac 1A were overrepresented by people >65 years of age (32%) and indigenous people (60%). Conclusions The Cardiac ARIA index demonstrated substantial inequity in access to cardiac services in Australia. This methodology can be used to inform cardiology health service planning and could be applied to other common disease states within other regions of the world.

Background: D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial (Long-Term Intervention with Pravastatin in Ischaemic Disease) in the context of other risk factors. Methods: LIPID randomized patients to placebo or pravastatin 40 mg/d 5 to 38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total. Results: Baseline D-dimer levels for 7863 patients were grouped by quartile (≤112, 112–173, 173–273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function, and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P P P P ≤0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR, 1.16; P =0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6. Conclusions: D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality independent of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years’ follow-up.

Background— It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. Methods and Results— We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38 153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81–0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72–0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels Conclusions— Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.

Background: Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. Methods: Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization–tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with ≥1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework. Results: Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678–0.682) to 0.700 (95% CI, 0.698–0.702; P P Conclusions: The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT00145925.

Background— We aimed to assess the long-term effects of treatment with statin therapy on all-cause mortality, cause-specific mortality, and cancer incidence from extended follow-up of the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial. Methods and Results— LIPID initially compared pravastatin and placebo over 6 years in 9014 patients with previous coronary heart disease. After the double-blind period, all patients were offered open-label statin therapy. Data were obtained over a further 10 years from 7721 patients, by direct contact for 2 years, by questionnaires thereafter, and from mortality and cancer registries. During extended follow-up, 85% assigned pravastatin and 84% assigned placebo took statin therapy. Patients assigned pravastatin maintained a significantly lower risk of death from coronary heart disease (relative risk [RR] 0.89; 95% confidence interval [CI], 0.81−0.97; P =0.009), from cardiovascular disease (RR, 0.88; 95% CI, 0.81−0.95; P =0.002), and from any cause (RR, 0.91; 95% CI, 0.85−0.97; absolute risk reduction, 2.6%; P =0.003).Cancer incidence was similar by original treatment group during the double-blind period (RR, 0.94; 95% CI, 0.82–1.08; P =0.41), later follow-up (RR, 1.02; 95% CI, 0.91–1.14; P =0.74), and overall (RR, 0.99; 95% CI, 0.91–1.08; P =0.83). There were no significant differences in cancer mortality, or in the incidence of organ-specific cancers. Cancer findings were confirmed in a meta-analysis with other large statin trials with extended follow-up. Conclusions— In LIPID, the absolute survival benefit from 6 years of pravastatin treatment appeared to be maintained for the next 10 years, with a similar risk of death among survivors in both groups after the initial period. Treatment with statins does not influence cancer or death from noncardiovascular causes during long-term follow-up.

Background— Elevated serum inflammatory marker levels are associated with a greater long-term risk of cardiovascular events. Because 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) may have an antiinflammatory action, it has been suggested that patients with elevated inflammatory marker levels may have a greater reduction in cardiovascular risk with statin treatment. Methods and Results— We evaluated the association between the white blood cell count (WBC) and coronary heart disease mortality during a mean follow-up of 6.0 years in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) Study, a clinical trial comparing pravastatin (40 mg/d) with a placebo in 9014 stable patients with previous myocardial infarction or unstable angina. An increase in baseline WBC was associated with greater coronary heart disease mortality in patients randomized to placebo (hazard ratio for 1×10 9 /L increase in WBC, 1.18; 95% CI, 1.12 to 1.25; P P =0.56; P for interaction=0.004). The numbers of coronary heart disease deaths prevented per 1000 patients treated with pravastatin were 0, 9, 30, and 38 for baseline WBC quartiles of 8.2×10 9 /L, respectively. WBC was a stronger predictor of this treatment benefit than the ratio of total to high-density lipoprotein cholesterol and a global measure of cardiac risk. There was also a greater reduction ( P =0.052) in the combined incidence of cardiovascular mortality, nonfatal myocardial infarction, and stroke with pravastatin as baseline WBC increased (by quartile: 3, 41, 61, and 60 events prevented per 1000 patients treated, respectively). Conclusions— These data support the hypothesis that individuals with evidence of inflammation may obtain a greater benefit from statin therapy.

Worldwide, noncommunicable diseases are the dominant cause of death, with atherosclerotic cardiovascular disease a major contributor.1 These deaths are spread across high- to low-income countries, with ≈1 in 3 of all cardiovascular disease deaths occurring in individuals aged

Background — The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that pravastatin significantly reduced mortality and coronary heart disease (CHD) events in 9014 patients with known CHD and total cholesterol 4.0 to 7.0 mmol/L at baseline. Secondary objectives included assessment of CHD event reduction according to lipid levels. Methods and Results — We investigated the relationships of baseline and on-study lipids with subsequent CHD events in separate Cox models. Treatment effect on CHD event reduction was examined by baseline lipids and after adjustment for on-study lipid levels. Baseline lipids were significant predictors of CHD events. The adjusted relative risk per mmol/L (on placebo) was 1.24 ( P =0.004) for total cholesterol, 1.28 ( P =0.002) for low-density lipoprotein cholesterol, and 0.52 ( P =0.004) for high-density lipoprotein cholesterol. Apolipoproteins A1 and B were strong predictors (each P =0.001). Pravastatin reduced the risk of the composite outcome of fatal CHD or nonfatal myocardial infarction by 24% (95% confidence interval [CI], 15% to 32%) and the expanded end point of fatal CHD, nonfatal myocardial infarction, unstable angina, or coronary revascularization by 17% (95% CI, 10% to 24%). Similar relative effects were observed for different categories of baseline lipids. The proportion of treatment effect explained by on-study lipid levels was 67% (95% CI, 27% to 106%) for the composite and 97% (95% CI, 49% to 145%) for the expanded end point. The most important lipids associated with event reduction were apolipoprotein B, low-density lipoprotein cholesterol, and the combination of total and high-density lipoprotein cholesterol. Conclusions — Changes in lipid levels can explain all or most of the observed benefit of pravastatin. Some treatment effect may also be mediated through nonlipid changes.

The evidence base demonstrating that statins reduce major events, including in people with diabetes mellitus,1 is arguably as robust as for any cardiovascular therapy. However, many individuals still experience end points despite the use of statins (the Figure). This “residual risk,” which is much higher in people with coexistent cardiovascular disease, is probably most appropriately expressed in absolute terms, acknowledging the development of atherosclerosis over decades rather than the duration of trials and its multifactorial causation. However, the residual risk provides the rationale for testing other lipid-modifying therapies in combination with statins. Figure. Vascular event rates, risk reduction, and residual risk despite statin use in major randomized controlled trials of statins in people with diabetes mellitus. CVD indicates cardiovascular disease; RRR, relative risk reduction; and ARR, absolute risk reduction. People with diabetes mellitus have both qualitative and quantitative lipid changes. They include increased levels of triglycerides, small dense low-density lipoprotein (LDL) particles, and apolipoprotein B, as well as a decrease in levels of high-density lipoprotein (HDL) cholesterol. Fibrates, which are peroxisome proliferator receptor-α agonists, not only reduce triglyceride levels and possibly LDL cholesterol and chylomicron remnants and elevate HDL cholesterol but also are anti-inflammatory. The major beneficial effect of statins is to decrease LDL cholesterol. However, lower levels of HDL cholesterol and possibly increasing levels of triglycerides still denote elevated risk in those taking statins,2,3 even when LDL cholesterol levels are very low,2 and particularly in those with diabetes mellitus.3 The hypothesis tested was whether, on a background of simvastatin 20 to 40 mg, major vascular events were reduced by fenofibrate, dosed according to baseline glomerular filtration rate.4 Overall, among 5518 subjects (mean age, 62 years; 31% female; …

BACKGROUND This study addressed the need for heparin administration to be continued for more than 24 hours after coronary thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). METHODS AND RESULTS A total of 241 patients with acute myocardial infarction were treated with 100 mg rt-PA and a bolus of 5,000 units i.v. heparin followed by 1,000 units/hr i.v. heparin for 24 hours. At 24 hours, 202 patients were randomized to continue intravenous heparin therapy (n = 99) in full dosage or to discontinue heparin therapy and begin an oral antiplatelet regimen of aspirin (300 mg/day) and dipyridamole (300 mg/day) (n = 103). On prospective recording, there were no differences in the pattern of chest pain, reinfarction, or bleeding complications. Coronary angiography on cardiac catheterization at 7-10 days showed no differences in patency of the infarct-related artery. The proportion of patients with total occlusion (TIMI grade 0-1) of the infarct-related artery was 18.9% in the heparin group and 19.8% in the aspirin and dipyridamole group. In the patients with an incompletely occluded infarct-related artery, the lumen was reduced by 69 +/- 2% of normal in the heparin group and 67 +/- 2% in the aspirin and dipyridamole group. Left ventricular function assessed on cardiac catheterization and radionuclide study at day 2 and at 1 month showed no differences between the two groups. Left ventricular ejection fraction on radionuclide ventriculography at 1 month was 52.4 +/- 1.2% in the heparin group and 51.9 +/- 1.2% in the aspirin and dipyridamole group. CONCLUSIONS We conclude that heparin therapy can be discontinued 24 hours after rt-PA therapy and replaced with an oral antiplatelet regimen without any adverse effects on chest pain, reinfarction, coronary patency, or left ventricular function.

Introduction: Alcohol intake is positively associated with high-density lipoprotein (HDL) cholesterol, however no studies have investigated the association with lipoprotein sub-classes using nuclear magnetic resonance spectroscopy (NMR). Hypothesis: We assessed the hypothesis that usual daily alcohol intake (volume), beverage type and drinking frequency influence plasma HDL sub-class concentrations as determined by NMR. Methods: Six hundred and ninety volunteers (389 women) aged 40 – 69 years at baseline (1990 –1994) participated in a cross-sectional study using the Melbourne Collaborative Cohort Study, Australia. Measures included self-reported alcohol intake using beverage-specific quantity-frequency questions (volume) and a drinking diary for previous week (frequency). Results: Median alcohol intake was 15.2 g/d (2.7, 32.0) for men and 1.0 g/d (0, 9.6) for women. Alcohol volume was positively associated with total HDL particle concentration in men and women. For men, a 10 g/d increment in alcohol intake increased total HDL particle concentration by 0.62 μmol/L (95% CI: 0.27, 0.98) and small HDL particle concentration by 0.34 μmol/L (0.01, 0.68). For women, total HDL particle concentration increased 1.06 μmol/L (0.60, 1.53) for every 10 g/d increment in alcohol intake. Alcohol volume was positively associated with large HDL particle concentration in premenopausal women [0.67 μmol/L (0.19, 1.15)] and small HDL particle concentration in postmenopausal women [0.82 μmol/L (0.14, 1.51)]. Beer, wine and spirits were all positively associated with total HDL concentration for men. Beer and wine were both positively associated with total HDL concentration for women. Drinking frequency was not associated with total HDL particle concentration or any of its’ sub-classes. Conclusions: Alcohol volume (and not drinking frequency) was positively associated with NMR-determined plasma total HDL particle concentration for men and women. These associations appeared to be regardless of beverage type, although comparison of beverage types was not possible for women. These results suggest that for any given weekly volume of alcohol, the number of drinking days does not influence HDL particle concentration.

Background— Limited data suggest that HMG-CoA reductase inhibitors (statins) reduce rates of kidney function loss. We performed this analysis to determine whether pravastatin reduced the rate of kidney function loss over ≈5 years in people with or at high risk for coronary disease. Methods and Results— This was a post hoc subgroup analysis of data from 3 randomized double-blind controlled trials comparing pravastatin 40 mg/d and placebo in subjects with a previous acute coronary syndrome or who were at high cardiovascular risk. The primary outcome was the rate of change in estimated glomerular filtration rate (GFR; in mL/min per 1.73 m 2 /y). The Modified Diet and Renal Disease Study (MDRD) and Cockcroft-Gault equations were used to estimate GFR. We studied 18 569 participants, 3402 (18.3%) of whom had moderate chronic kidney disease as defined by an estimated GFR of 30 to 59.9 mL/min per 1.73 m 2 body surface area. In subjects with moderate chronic kidney disease at baseline, pravastatin reduced the adjusted rate of kidney function loss by ≈34%, although the absolute reduction in the rate of loss was small (0.22 mL/min per 1.73 m 2 /y by MDRD-GFR; 95% CI, 0.07 to 0.37). Pravastatin did not reduce the frequency of ≥25% decreases in kidney function in this group when MDRD-GFR was used to estimate GFR (relative risk [RR], 0.84; 95% CI, 0.66 to 1.06). When all 18 569 subjects were considered, pravastatin reduced the adjusted rate of kidney function loss by 8% (0.08 mL/min per 1.73 m 2 /y by MDRD-GFR; 95% CI, 0.01 to 0.15) and the risk of acute renal failure (RR, 0.60; 95% CI, 0.41 to 0.86) but did not significantly reduce the frequency of a ≥25% decline in kidney function by MDRD-GFR (RR, 0.94; 95% CI, 0.88 to 1.01). Conclusions— Pravastatin modestly reduced the rate of kidney function loss in people with or at risk for cardiovascular disease. However, the primary indication for the use of statins in people with or at risk for coronary events remains the reduction in mortality that results from their use.

Background— Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results— We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin (40 mg daily) versus placebo. Of 19 700 subjects, 4491 (22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m 2 body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome (adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome (HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function (HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD (adjusted HR 0.86, 95% CI 0.74 to 1.00, P =0.045). Conclusions— Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

The occurrence of stroke increases with age, particularly affecting the older elderly, a population also at higher risk for coronary heart disease (CHD). Epidemiological and observational studies have not shown a clear association between cholesterol levels and all causes of stroke. Nonetheless, large, long-term statin trials in patients with established CHD or at high risk for CHD have shown that statins decrease stroke incidence in these populations. Combined data from 9 trials including 70 070 patients indicated relative and absolute risk reductions for stroke of 21% and 0.9%, respectively, with statins. The number of strokes prevented per 1000 patients treated for 5 years in patients with CHD is 9 for statins, compared with 17.3 for antiplatelet agents. Statins have not yet been shown to reduce stroke risk in the typical general population without known CHD, nor have they been shown to prevent recurrent stroke in patients with prior stroke. Potential reasons for the effects of statins on stroke and the non- cholesterol-lowering mechanisms that may be involved are discussed. Treatment strategies based on global cardiovascular risk may be most effective. Additional studies in patients representative of the typical stroke population are needed. (Circulation. 2004;109(suppl III):III-44 -III-49.)

Background — Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data. Methods and Results — The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3× the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo. Conclusions — This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.

Background — In two large secondary prevention trials of pravastatin, risk reduction was not significant in participants who had low baseline LDL-C concentrations (that is, Methods and Results — Among 13 173 participants with coronary heart disease (CHD), 2607 had baseline LDL-C 2 ); and pravastatin lowered their LDL-C by 36 mg/dL (32%) versus 45 mg/dL (29%). During 5.8-year (mean) follow-up, HDL-C and triglycerides were both significantly stronger predictors of recurrent CHD events in participants with LDL-C P =0.004), significantly different from the effect in nondiabetic participants with low LDL-C ( P interaction, 0.005) (event rate, 21%; relative risk, 1.06 [95% CI, 0.89 to 1.27]). There were trends toward risk reduction in smokers and in those with low HDL-C, Conclusions — Among patients with CHD who have low LDL-C, diabetics have much higher subsequent CHD event rates than do nondiabetics. Pravastatin reduced the event rate in diabetics to that of nondiabetic participants. The results also suggest enhanced therapeutic potential for improving HDL-C and triglycerides in patients with CHD who have low LDL-C concentrations.