David D. Waters

Effects of estrogen replacement on the progression of coronary-artery atherosclerosis

Background Heart disease is a major cause of illness and death in women. To understand better the role of estrogen in the treatment and prevention of heart disease, more information is needed about its effects on coronary atherosclerosis and the extent to which concomitant progestin therapy may modify these effects. Methods We randomly assigned a total of 309 women with angiographically verified coronary disease to receive 0.625 mg of conjugated estrogen per day, 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate per day, or placebo. The women were followed for a mean (±SD) of 3.2±0.6 years. Base-line and follow-up coronary angiograms were analyzed by quantitative methods. Results Estrogen and estrogen plus medroxyprogesterone acetate produced significant reductions in low-density lipoprotein cholesterol levels (9.4 percent and 16.5 percent, respectively) and significant increases in high-density lipoprotein cholesterol levels (18.8 percent and 14.2 percent, respectively); however,...

Aspirin, heparin, or both to treat acute unstable angina

We tested the usefulness of aspirin (325 mg twice daily), heparin (1000 units per hour by intravenous infusion), and a combination of the two in the early management of acute unstable angina pectoris in a double-blind, randomized, placebo-controlled trial involving 479 patients. The patients entered the study as soon as possible after hospital admission (at a mean [+/- SD] of 7.9 +/- 8.0 hours after the last episode of pain), and the study was ended after 6 +/- 3 days, when definitive therapy had been selected. Major end points--refractory angina, myocardial infarction, and death--occurred in 23, 12, and 1.7 percent of the 118 patients receiving placebo, respectively. Heparin was associated with a decrease in the occurrence of refractory angina (P = 0.002). The incidence of myocardial infarction was significantly reduced in the groups receiving aspirin (3 percent; P = 0.01), heparin (0.8 percent; P less than 0.001), and aspirin plus heparin (1.6 percent, P = 0.003), and no deaths occurred in these groups. There were too few deaths overall to permit evaluation of the effect of treatment on this end point. The combination of aspirin and heparin had no greater protective effect than heparin alone but was associated with slightly more serious bleeding (3.3 vs. 1.7 percent). We conclude that in the acute phase of unstable angina, either aspirin or heparin treatment is associated with a reduced incidence of myocardial infarction, and there is a trend favoring heparin over aspirin. Heparin treatment is also associated with a reduced incidence of refractory angina.

Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.

CONTEXT A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus. OBJECTIVE To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. DATA SOURCES We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators. STUDY SELECTION We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year. DATA EXTRACTION Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I(2) statistic. RESULTS In 5 statin trials with 32,752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. CONCLUSION In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.

Prognostic value of exercise testing soon after myocardial infarction.

The prognostic value of a limited treadmill exercises test performed one day before hospital discharge after acute myocardial infarction was studied in 210 consecutive patients who had no over heart failure and had been free of chest pain for at least four days. No complications occurred. During a one-year follow-up period 28 of 43 patients (65 per cent) who had chest pain during the test reported angina, as compared with 60 of 167 (36 per cent) who had no chest pain during test (P less than 0.001). The one-year mortality rates were 2.1 per cent (three of 146) in patients without changes in the S-T segment during exercise and 27 per cent (17 of 64) in those with depression of the S-T segment (P less than 0.001). Sudden death occurred in one of 146 (0.7 per cent) patients who showed no change in the S-T segment and in 10 of 64 (16 per cent) with depression of the segment (P less than 0.001). Thus, a limited treadmill exercise test performed before hospital discharge after acute myocardial infarction is safe and can predict mortality in the subsequent year.

Progression of Atherosclerosis as Assessed by Carotid Intima-Media Thickness in Patients With HIV Infection

Background—HIV-infected patients may be at increased risk for coronary events. The purpose of this study was to identify predictors of carotid intima-media thickness (IMT) in HIV patients at baseline and to measure IMT progression over 1 year. Methods and Results—We measured blood lipids, inflammatory markers, and IMT in 148 HIV-infected adults (mean age, 45±8 years) and in 63 age- and sex-matched HIV-uninfected control subjects. The mean duration of HIV infection was 11 years, and the median duration of protease inhibitor treatment was 3.3 years. Mean baseline IMT was 0.91±0.33 mm in HIV patients and 0.74±0.17 mm in control subjects (P =0.0001). Multivariable predictors of baseline IMT in HIV patients were age (P <0.001), LDL cholesterol (P <0.001), cigarette pack-years (P =0.005), Latino race (P =0.062), and hypertension (P =0.074). When the control group was added to the analysis, HIV infection was an independent predictor of IMT (P =0.001). The rate of progression among the 121 HIV patients with a repeated IMT measurement at 1 year was 0.074±0.13 mm, compared with −0.006±0.05 mm in 27 control subjects (P =0.002). Age (P <0.001), Latino race (P =0.02), and nadir CD4 count ≤200 (P =0.082) were multivariable predictors of IMT progression. Conclusions—Carotid IMT is higher in HIV patients than in age-matched control subjects and progresses much more rapidly than previously reported rates in non-HIV cohorts. In HIV patients, carotid IMT is associated with classic coronary risk factors and with nadir CD4 count ≤200, suggesting that immunodeficiency and traditional coronary risk factors may contribute to atherosclerosis.

Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention Trial.

BACKGROUND 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are widely prescribed for hyperlipidemia, yet their effect on the evolution of coronary atherosclerosis has not been defined. METHODS AND RESULTS To address this issue, 331 patients with diffuse but not necessarily severe coronary atherosclerosis documented on a recent arteriogram and with fasting serum cholesterol between 220 and 300 mg/dL were enrolled in a randomized, double-blind, placebo-controlled trial. All patients received intensive dietary counseling. Lovastatin or placebo was begun at 20 mg/d and was titrated to 40 and 80 mg during the first 16 weeks to attain a fasting low-density lipoprotein (LDL) cholesterol < or = 130 mg/dL. The mean lovastatin dose was 36 mg/d. Coronary arteriography was repeated after 2 years. In 299 patients (90%), 3858 coronary segments containing 2309 stenoses were measured blindly on pairs of films with an automated computerized quantitative system. Total and LDL cholesterol decreased by 21 +/- 11% and 29 +/- 11%, respectively, in the lovastatin-treated group but changed by < 2% in placebo patients. The primary end point, coronary change score, defined as the per-patient mean of the minimum lumen diameter changes (follow-up minus baseline angiogram) for all lesions measured, excluding those < 25% on both films, worsened by 0.09 +/- 0.16 mm in the placebo group and by 0.05 +/- 0.13 mm in the lovastatin group (P = .01). Progression (a worsening in minimum diameter of one or more stenoses by > or = 0.4 mm) with no regression at other sites occurred in 48 of 146 lovastatin and 76 of 153 placebo patients (33% versus 50%, P = .003). New coronary lesions developed in 23 lovastatin and 49 placebo patients (P = .001). The beneficial effect of treatment was most pronounced in the more numerous, milder lesions and in patients whose baseline total or LDL cholesterol levels were above the group median. CONCLUSIONS Lovastatin slows the progression of coronary atherosclerosis and inhibits the development of new coronary lesions.

Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: The Treating To New Targets (TNT) study

OBJECTIVE—The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS—A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non–procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS—End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58–0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48–0.98], P = 0.037) and any cardiovascular event (0.85 [0.73–1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. CONCLUSIONS—Among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg.

Reactivation of Unstable Angina after the Discontinuation of Heparin

BACKGROUND Heparin is an effective, widely used treatment for unstable angina. Among patients enrolled in a double-blind, randomized, placebo-controlled trial comparing intravenous heparin, aspirin, both treatments, and neither during the acute phase of unstable angina, we encountered patients in whom unstable angina was reactivated after heparin was discontinued. METHODS The study population included 403 of the original 479 patients in the trial who had completed six days of blinded therapy without refractory angina or myocardial infarction. After the discontinuation of therapy, clinical events, including reactivation of unstable angina and myocardial infarction occurring within 96 hours after hospitalization, were closely monitored. RESULTS Early reactivation occurred in 14 of the 107 patients who received heparin alone, as compared with only 5 patients in each of the other three study groups (P less than 0.01). These reactivations required urgent intervention (thrombolysis, angioplasty, or coronary-bypass surgery) in 11 patients treated with heparin alone, but in only 2 patients in the other groups combined (P less than 0.01). Four of the six patients who had a myocardial infarction during a reactivation of their disease were in the heparin group. Reactivations in this group occurred in a cluster a mean (+/- SD) of 9.5 +/- 5 hours after the discontinuation of the study drug but were randomly distributed over the initial 96 hours in the other three groups. CONCLUSIONS Although heparin is beneficial in treating unstable angina, the disease process may be reactivated within hours of the discontinuation of this drug. Concomitant therapy with aspirin may prevent this withdrawal phenomenon.

Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study

BACKGROUND Despite the prognostic value of metabolic syndrome for predicting cardiovascular events, few trials have investigated the effects of statin therapy on cardiovascular morbidity and mortality in patients with the metabolic syndrome. Our post hoc analysis of the Treating to New Targets (TNT) study assessed whether intensive lowering of low-density lipoprotein cholesterol with high-dose atorvastatin therapy results in cardiovascular benefits for patients with both coronary heart disease and the metabolic syndrome. METHODS The TNT study was a prospective, double blind, parallel-group trial done at 256 sites in 14 countries between April, 1998, and August, 2004, with a median follow-up of 4.9 years. 10,001 patients were enrolled aged 35-75 years with clinically evident coronary heart disease. Our analysis includes 5584 patients with metabolic syndrome based on the 2005 NCEP ATP III criteria. Patients were randomly assigned to receive either atorvastatin 10 mg per day (n=2820) or 80 mg per day (n=2764). The primary outcome measure was time to first major cardiovascular event, defined as death from coronary heart disease, non-fatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or non-fatal stroke. FINDINGS In patients with coronary heart disease and metabolic syndrome, mean on-treatment low-density lipoprotein cholesterol concentrations at 3 months were 2.6 mmol/L (99.3 mg/dL) with atorvastatin 10 mg, and 1.9 mmol/L (72.6 mg/dL) with atorvastatin 80 mg. At a median follow-up of 4.9 years, major cardiovascular events occurred in 367 (13%) patients receiving atorvastatin 10 mg, compared with 262 (9.5%) receiving atorvastatin 80 mg (hazard ratio 0.71; 95% CI 0.61-0.84; p<0.0001). Irrespective of treatment assignment, significantly more patients with metabolic syndrome (11.3%) had a major cardiovascular event at a median of 4.9 years than those without metabolic syndrome (8.0%; hazard ratio 1.44; 95% CI 1.26-1.64; p<0.0001). This increased risk was significantly reduced by intensive therapy with atorvastatin 80 mg beyond that achieved with atorvastatin 10 mg. INTERPRETATION These data indicate that patients with coronary heart disease and metabolic syndrome derive incremental benefit from high-dose atorvastatin therapy, irrespective of the presence of diabetes.

Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events.

BackgroundThere is considerable evidence that remnants of triglyceride-rich lipoproteins may be particularly atherogenic. Methods and ResultsLevels of lipoprotein lipids and of apolipoprotein B in low-density lipoproteins were measured in 335 men and women enrolled in a study in which quantitative coronary angiography was carried out at 2-year intervals. Clinical events related to coronary disease occurred in 129 patients during the trial and in the subsequent follow-up period of 4 to 6 years. In multivariate analysis controlled for a number of nonlipid risk factors, high-density lipoprotein cholesterol was inversely related to the mean percentage increase in coronary artery stenosis in both men and women. Neither plasma triglycerides nor low-density lipoprotein cholesterol, triglycerides, or apolipoprotein B was related to change in stenosis, but a measure of remnants of triglyceride-rich lipoproteins, which included cholesterol in intermediatedensity lipoproteins, was directly related to lesion progression. The same relations for these measures of plasma lipoprotein concentrations were found to hold for clinical events related to coronary artery atherosclerosis. ConclusionsIn patients with established coronary heart disease, increased levels of remnants of triglyceride-rich lipoproteins and decreased levels of high-density lipoproteins appear to promote progression of coronary artery atherosclerosis, which in turn may lead to an untoward clinical event. No such relation could be shown for the level of components of low-density lipoproteins. These and other observations call for reevaluation of relations between particular species of lipoproteins containing apolipoprotein B and the pathogenesis of coronary artery atherosclerosis and coronary heart disease.