Management of dyslipidemia for cardiovascular disease risk reduction: synopsis of the 2014 U. S. Department of Veterans Affairs and U. S. Department of Defense clinical practice guideline

DESCRIPTION: In December 2014, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline for the management of dyslipidemia for cardiovascular disease risk reduction in adults. This synopsis summarizes the major recommendations. METHODS: On 30 September 2013, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions, systematically searched and evaluated the literature, developed a simple 1-page algorithm, and rated each of 26 recommendations by using the Grading of Recommendations Assessment, Development, and Evaluation system. RECOMMENDATIONS: This synopsis summarizes key features of the guideline in 5 areas: elimination of treatment targets, additional tests for risk prediction, primary and secondary prevention, and laboratory testing.

Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.

BACKGROUND: Elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events. Statin therapy reduces the level of C-reactive protein independently of its effect on lipid levels. We hypothesized that statins might prevent coronary events in persons with elevated C-reactive protein levels who did not have overt hyperlipidemia. METHODS: The level of C-reactive protein was measured at base line and after one year in 5742 participants in a five-year randomized trial of lovastatin for the primary prevention of acute coronary events. RESULTS: The rates of coronary events increased significantly with increases in the base-line levels of C-reactive protein. Lovastatin therapy reduced the C-reactive protein level by 14.8 percent (P<0.001), an effect not explained by lovastatin-induced changes in the lipid profile. As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol was higher than the median ratio, regardless of the level of C-reactive protein (number needed to treat for five years to prevent 1 event, 47; P=0.005). However, lovastatin was also effective among those with a ratio of total to HDL cholesterol that was lower than the median and a C-reactive protein level higher than the median (number needed to treat, 43; P=0.02). In contrast, lovastatin was ineffective among participants with a ratio of total to HDL cholesterol and a C-reactive protein level that were both lower than the median (number needed to treat, 983; P=0.80). CONCLUSIONS: Statin therapy may be effective in the primary prevention of coronary events among subjects with relatively low lipid levels but with elevated levels of C-reactive protein.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin.

This study presents the long-term safety data from AFCAPS/TexCAPS, the first primary prevention trial to demonstrate that men and women with average levels of low-density lipoprotein cholesterol (LDL-C) and below average levels of high-density lipoprotein cholesterol (HDL-C) can significantly benefit from long-term treatment to lower LDL-C; lovastatin 20 to 40 mg/day reduced the risk of a first acute major coronary event (fatal or nonfatal myocardial infarction, unstable angina, or sudden death) by 37% (p = 0.00008). This double-blind randomized, placebo-controlled trial, in 6,605 generally healthy middle-aged and older men and women, had prespecified end point and cancer analyses. All analyses were intention-to-treat. Safety monitoring included history, physical examination, and laboratory studies (including hepatic transaminases and creatine phosphokinase [CPK]). All participants, even those who discontinued treatment, were contacted annually for vital status, cardiovascular events, and cancer history. After an average of 5.2 years of follow-up, there were 157 deaths (80 receiving lovastatin and 77 receiving placebo; relative risk [RR] 1.04; 95% confidence interval [CI] 0.76 to 1.42; p = 0.82); of which 115 were noncardiovascular (RR 1.21; CI 0.84 to 1.74; p = 0.31), and of these, 82 were due to cancer (RR 1.41; CI 0.91 to 2.19; p = 0.13). There were no significant differences between treatment groups in overall cancer rates, discontinuations for noncardiovascular adverse experiences, or clinically important elevations of hepatic transaminases or CPK. Among those who used cytochrome P450 isoform (CYP3A4) inhibitors, there were no treatment group differences in the frequency of clinically important muscle-related adverse events. Treatment with lovastatin 20 to 40 mg daily for primary prevention of coronary heart disease was well tolerated and reduced the risk of first acute coronary events without increasing the risk of either noncardiovascular mortality or cancer.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): efficacy and tolerability of long-term treatment with lovastatin in women.

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first coronary heart disease (CHD) primary prevention trial of the cholesterol-reducing agents called "statins" to include women. For 5608 men and 997 postmenopausal women without clinical evidence of cardiovascular disease (CVD) who had average low-density lipoprotein cholesterol (LDL-C) and below average high-density lipoprotein cholesterol (HDL-C), 20-40 mg/day lovastatin reduced first acute major coronary events (AMCEs) 37% (for those receiving placebo and lovastatin, respectively, 183 and 116 first AMCEs defined as fatal or nonfatal myocardial infarction [MI], unstable angina, or sudden cardiac death; relative risk [RR] 0.63; 95% confidence interval [95% CI] 0.50, 0.79; p < 0.001). Statistically significant reductions in prespecified secondary end points (coronary revascularizations, unstable angina, MI, cardiovascular end point events, and coronary end point events) were also associated with lovastatin treatment in the overall cohort. This paper provides results in women, a prespecified subgroup. Among women, 20-40 mg/day lovastatin reduced LDL-C 25% and increased HDLC 9% (p < 0.001). A prespecified analysis revealed consistency with the overall results regardless of gender (i.e., there were no statistical differences between men and women in risk reduction for first AMCEs with lovastatin). However, the number of women who had an AMCE was small, and there was insufficient power to detect a treatment group difference among women (7 of 499 vs. 13 of 498 first AMCEs in those receiving lovastatin and placebo, respectively; RR 0.54; 95% CI 0.22, 1.35; p = 0.183). Numerical reductions in all prespecified secondary end points were observed for women treated with lovastatin, but again, the numbers of events were small and the differences were not statistically significant. Chronic long-term treatment with lovastatin was well tolerated, with no treatment group differences in the frequency of cancer, muscle symptoms, and clinically important liver enzyme elevations. In AFCAPS/TexCAPS, a consistent pattern of numerical reductions in all prespecified primary and secondary cardiovascular end points was observed in women treated with lovastatin for primary prevention of CHD. However, because of the small number of events, there was insufficient power to detect significant treatment group differences. Lovastatin treatment was associated with statistically significant decreases in LDL-C and increases in HDL-C, and chronic long-term treatment with 20-40 mg/day lovastatin was well tolerated in women.

Application of the National Cholesterol Education Program and joint European treatment criteria and clinical benefit in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

AIMS: The Air Force/Texas Coronary Atherosclerosis Prevention Study reported that diet with lovastatin, 20-40 mg daily, reduced the risk for a first coronary event by 37%. Because only 17% of this cohort would have qualified for drug therapy according to current U.S. guidelines, we assessed clinical benefit by risk categories. METHODS AND RESULTS: The main outcome measures were event rates of first acute major coronary events stratified by National Cholesterol Education Program and European criteria and target goal. Both those who would and would not be eligible for drug therapy, according to National Cholesterol Education Program guidelines, benefited from intervention. As expected, drug-eligible participants (event rate: lovastatin 1%/year, placebo 1.87%/year [relative risk 0.53, 95% confidence interval: 0.33, 0.84]) were at greater absolute risk for acute major coronary events than non-eligible participants (lovastatin 0.62%/year, placebo 0.93%/year [relative risk 0.67, 95% confidence interval: 0.51, 0.88]). Similar results were found using European guidelines for coronary risk management. Treatment to a target goal suggested a non-significant trend to greater benefit. CONCLUSIONS: The consistent relative benefit across risk categories suggests that it may be possible to improve identification of at-risk persons who would benefit from primary prevention, and to recommend appropriate goals of such treatment.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): baseline characteristics and comparison with USA population.

BACKGROUND: Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) demonstrated that treatment with lovastatin, in addition to modifications of diet and lifestyle, reduced the rate of first acute major coronary events compared with placebo in a cohort that included participants with average to mildly elevated total levels of cholesterol, and below average levels of high-density lipoprotein cholesterol, women, and elderly subjects. OBJECTIVE: To describe the baseline characteristics of the study's cohort. DESIGN: This was a double-blind, placebo-controlled, primary-prevention trial in which Americans with average to mildly elevated total levels of cholesterol [4.65-6.83 mmol/l (180-264 mg/dl)] and no clinical evidence of atherosclerotic cardiovascular disease were randomly allocated either 20-40 mg/day lovastatin or placebo in addition to a low-saturated fat, low-cholesterol diet. Baseline characteristics of the study cohort are described, and the characteristics of a USA reference population based upon NHANES III data are provided for comparison. RESULTS: The study includes 5608 men (85%) and 997 women (15%) with mean total cholesterol level 5.71 +/- 0.54 mmol/l (221 +/- 21 mg/dl), low-density lipoprotein cholesterol level 3.88 +/- 0.44 mmol/l (150 +/- 17 mg/dl), high-density lipoprotein cholesterol 0.96 +/- 0.15 mmol/l (37 +/- 6 mg/dl), and median triglyceride level 1.78 +/- 0.86 mmol/l (158 +/- 76 mg/dl). The mean age is 58 years (ranges 45-73 years for men and 55- 73 years for women). The participants are 89% white, 7% Hispanic, and 3% black. CONCLUSION: Results from AFCAPS/TexCAPS will be applicable to large segments of populations; in the USA alone, eight million share the demographic and baseline-lipid-level characteristics of the study cohort.

Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

BACKGROUND: The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs. METHODS AND RESULTS: With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed. CONCLUSIONS: Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.

Forecasting patient outcomes in the management of hyperlipidemia.

BACKGROUND: To forecast adult patient outcomes in the management of hyperlipidemia using adult National Health and Examination Survey III (NHANES III) population statistics and National Cholesterol Education Program (NCEP) guidelines for goals of therapy. METHODS: Review of the hyperlipidemia drug therapy English-language medical literature with emphasis on randomized controlled trials of more than 6 weeks' duration published in the last 7 years, product package inserts, US Food and Drug Administration submission information, and NHANES III population statistics. Data were extracted from studies of lipid-lowering therapy to modify low-density lipoprotein (LDL) levels for primary and secondary prevention of coronary heart disease. The data that were evaluated included sample size, study design, therapeutic intervention, length of study, percentage change in LDL levels, and patient demographics. RESULTS: Cumulative frequency curves of the LDL distribution among the US adult population were constructed. The mean efficacy of drug therapy from qualified studies was used to extrapolate the percentage of the population expected to respond to the intervention and to forecast the patient outcome. CONCLUSIONS: A useful tool for clinicians was constructed to approximate the percentage of patients, based on risk stratification, who would reach NCEP target goal after a given pharmacotherapeutic intervention to decrease LDL levels.

Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.

CONTEXT: Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. OBJECTIVE: To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Outpatient clinics in Texas. PARTICIPANTS: A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). INTERVENTION: Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. MAIN OUTCOME MEASURES: First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. RESULTS: After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. CONCLUSIONS: Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.

Design & rationale of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, double-blind, placebo-controlled primary prevention trial. It is designed to test the hypothesis that in addition to a lipid-lowering diet, treatment with lovastatin is more effective than placebo in reducing acute major coronary events (i.e., sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina) in a cohort with normal to mildly elevated total (180 to 264 mg/dl) and low-density lipoprotein (LDL) cholesterol (130 to 190 mg/dl) and low high-density lipoprotein (HDL) cholesterol (< or =45 mg/dl for men and < or =47 mg/dl for women). Two sites in Texas, Lackland Air Force Base in San Antonio and the University of North Texas Health Science Center in Fort Worth, will conduct the study. After at least 12 weeks of an American Heart Association Step 1 diet and 2 weeks placebo run-in, 6,605 men and women, ages 45 to 73 and 55 to 73 years, respectively, without clinical evidence of coronary heart disease, are randomized in equal numbers to either lovastatin (20 mg/day) or placebo. Study procedures maintain the blind, allowing titration of lovastatin from 20 to 40 mg/day to achieve an LDL cholesterol goal of < or = 110 mg/dl. All participants are followed until study completion, when 320 participants have had a primary end point or a minimum of 5 years after the last participant is randomized, whichever occurs last. All end points are adjudicated by an independent committee using prespecified criteria. Unique features of this trial are (1) the inclusion of unstable angina in the primary end point to reflect the increasing trend to treat coronary heart disease aggressively before a myocardial infarction has occurred, (2) aggressive pharmacologic intervention, with titration, to attain an LDL cholesterol goal less than the current National Cholesterol Education Panel guidelines for primary prevention, and (3) a cohort that includes women, the elderly, and those with mild to moderate hyperlipidemia and low HDL cholesterol. Compared with earlier studies, results will be applicable to a broader population and may help clarify the role of aggressive LDL cholesterol reduction measures in primary prevention. Treatment of this population is likely to realize the greatest cumulative long-term benefit in the prevention of acute major coronary events.

Gas-chromatographic assay for heme oxygenase activity.

We have developed an improved assay for microsomal heme oxygenase activity, based on the enzymic release of CO from the alpha-methene bridge of hemin and the quantitation of CO by gas chromatography. The within-run coefficient of variation (CV) of heme oxygenase assays in microsomes from rat tissues (liver, kidney) averaged 8%; the between-run CV averaged 15%. The detection limit for heme oxygenase activity was approximately 1 nmol/h per milligram of microsomal protein. Gas-chromatographic assays of heme oxygenase activities in rat tissues correlated well (r = 0.94) with results by a spectrophotometric assay based on bilirubin production. In untreated rats, heme oxygenase activity averaged 7 +/- 3 nmol/h per milligram of protein (n = 36) in kidney microsomes and 14 +/- 5 nmol/h per milligram of protein (n = 17) in liver microsomes. Heme oxygenase activity was increased 10-fold in kidney microsomes and threefold in liver microsomes from rats killed 17 h after subcutaneous injection of NiCl2 (0.5 mmol/kg body wt). These findings illustrate the efficacy of the gas-chromatographic assay for measuring xenobiotic effects on heme oxygenase activity.