State of the art approach to managing angina and ischemia: tailoring treatment to the evidence.

Stable angina represents a chronic and often debilitating condition that affects daily activities and quality of life in patients with chronic coronary syndromes (CCS). Current European Society of Cardiology guidelines recommend a four-step approach for the medical treatment of patients taking into consideration hemodynamic variables (heart rate and blood pressure) and the presence or absence of left ventricular dysfunction. However, CCS patients often have several comorbidities and risk factors. Thus, a tailored approach that takes into consideration patient risk factors and comorbidities may have additional benefits beyond angina relief. This is a state of the art review of stable angina treatment based on the currently available evidence.

Impact of myocardial ischemia on myocardial revascularization in stable ischemic heart disease. Lessons from the COURAGE and FAME 2 trials.

In patients with stable ischemic heart disease (SIHD), myocardial revascularization should be performed to either improve survival or improve symptoms and functional status among patients who are not well controlled with optimal medical therapy (OMT). A general consensus exists on the core elements of OMT, which include both lifestyle intervention and intensive secondary prevention with proven pharmacotherapies. By contrast, however, there is less general agreement as to what constitutes the optimal approach to revascularization in SIHD patients. The COURAGE and FAME 2 randomized trials form the foundation of the current clinical evidence base and raise the important question: "What is the impact of myocardial ischemia on myocardial revascularization in stable ischemic heart disease?"

Interpretation of new treatment guidelines for non-ST-segment elevation acute coronary syndromes: "ischemia-guided" versus "early invasive" strategies.

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines has recently published recommendations regarding the diagnosis and management of patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). Conventional therapy for non-ST-segment elevation acute coronary syndrome (NSTE ACS) has traditionally employed an "ischemia-guided" approach in which diagnostic cardiac catheterization and revascularization are only used in patients with objective-evidence of residual myocardial ischemia as identified by recurrent symptoms or provocative stress testing. More recent studies, however, have demonstrated improved clinical outcomes with the use of an "early invasive" approach, employing routine coronary angiography early in the patient's hospital course, followed by percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery where appropriate. Improved clinical outcomes associated with an "early invasive" strategy may have evolved as a consequence of recent advances in both adjunctive pharmacotherapy and revascularization technique. For example, use of GP IIb/IIIa inhibitors and/or low-molecular-weight heparin prior to catheterization have been shown to reduce clinical events in NSTE ACS patients, and may reduce the risk of an invasive approach by plaque passivation prior to interventional therapy. Perhaps more importantly, the combined use of GP IIb/IIIa inhibitors and intracoronary stenting may reduce the potential early hazard of an invasive approach by specifically decreasing the incidence of death and non-fatal myocardial infarction associated with percutaneous intervention. In spite of the benefits of this synergistic combination of pharmacology and mechanical revascularization, risk stratification remains important in identifying high-risk individuals most likely to benefit from an "early invasive" approach.

The Connecticut Cardiovascular Consortium: a unique, state-wide research collaboration to advance clinical outcomes in patients with heart disease.

The establishment of "best clinical practices" founded upon evidence-based medicine has become an increasingly important priority. Frequently, management guidelines are derived from published research data and disseminated among practitioners to help optimize patient care. The ultimate clinical impact of these guidelines in the "real world," however, is often clouded by an incomplete assessment of patient outcomes throughout the continuum of health-care delivery models. In order to address this gap in clinical outcome assessment, we propose to establish the Connecticut Cardiovascular Consortium. The Consortium will consist of a collaborative partnership among all 31 Connecticut hospitals working in concert with Connecticut Office of Health Care Access (OHCA). The primary objective of the Consortium will be to assess, compare, and optimize clinical outcomes among Connecticut residents with cardiovascular disease. As an initial goal for the Consortium, we further propose to undertake a prospective, observational study of Connecticut residents who present with ST Segment Elevation Acute Myocardial Infarction (STEMI). Recent advances in pharmacologic and mechanical reperfusion for STEMI have resulted in a need to define the optimal use of these therapies in the community at large. The primary purpose of this study will be to determine the relative merits of different treatment patterns for STEMI with regard to the use of fibrinolytic therapy and percutaneous coronary intervention (PCI). Particular emphasis will be placed on assessing the relative benefits of urgent mechanical revascularization performed at the state's seven tertiary facilities with PCI capability compared to all other treatment modalities. Successful completion of this unique collaborative endeavor is expected to have significant impact on improved patient care and on current health-care policy for medical resource allocation. Moreover, continued collaboration of health-care providers within the Connecticut Cardiovascular Consortium infrastructure should serve as a useful mechanism for ongoing improvements in evidence-based cardiovascular medicine and clinical research in the state of Connecticut.

Interpreting new treatment guidelines for non-ST-segment elevation acute coronary syndromes.

The American College of Cardiology/American Heart Association Task Force on Practice Guidelines has published recommendations on the diagnosis and treatment of patients with known or suspected unstable angina and non-ST-segment elevation myocardial infarction. The acute ischemia pathway presented in these guidelines encompasses both an early invasive strategy and an early conservative strategy. There are now 4 randomized, controlled trials that have compared the routine early invasive strategy with the selective-invasive or ischemia-guided strategy (Thrombolysis in Myocardial Infarction [TIMI] IIIB, Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital [VANQWISH], Fragmin and Fast Revascularization During Instability in Coronary Artery Disease [FRISC] II, and Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy [TACTICS]-TIMI 18). The most relevant of these studies to current clinical practice are the FRISC II and TACTICS-TIMI 18 studies. The data from these studies indicate that ST-segment depression or elevated levels of troponin or the MB isoenzyme of creatinine kinase are markers of increased risk and that such patients would benefit from early revascularization. However, the data further suggest that aggressive antiplatelet, antithrombin, and anti-ischemic therapies are also important. Although FRISC II and TACTICS-TIMI 18 support an early invasive approach in most patients (ie, intermediate- and high-risk patients) with non-ST-segment elevation acute coronary syndromes (ACS), all 4 trials support a more conservative approach in those without electrocardiographic changes or enzyme elevations, notably the use of intensive antiplatelet, antithrombotic, and anti-ischemic therapy combined with careful clinical assessment and provocative testing. Patients then undergo catheterization and revascularization only if spontaneous angina occurs or if there is electrocardiographic, enzymatic, or other objective evidence of stress-induced myocardial ischemia. We conclude that tailoring the early initial therapy in hospital to the level of risk is essential to optimizing efficacy and clinical outcomes in this challenging, but common group of ACS patients.

Small peptide GP IIb/IIIa receptor inhibitors as upstream therapy in non-ST-segment elevation acute coronary syndromes: results of the PURSUIT, PRISM, PRISM-PLUS, TACTICS, and PARAGON trials.

The primary pathophysiologic mechanism underlying all non-ST-segment elevation acute coronary syndromes (NSTE ACS) is the formation of platelet-rich coronary thrombi in response to spontaneous or intervention-induced endothelial damage with exposure of subendothelial substrates. Antagonists of the glycoprotein (GP) IIb/IIIa receptor ameliorate this process by blocking the final common pathway for platelet aggregation. Based upon collective data in over 24,000 patients, clinical trials have demonstrated that treatment of NSTE ACS patients with GP IIb/IIIa agents results in an approximate 12% relative risk reduction in the incidence of death or myocardial infarction at 30 days. The magnitude of this clinical benefit is increased in patients who are troponin-positive and who are referred for early percutaneous intervention. Potential benefits of GP IIb/IIIa inhibitor use must be weighed against an increased risk of bleeding. Ongoing controversies exist concerning the relative efficacy of different GP IIb/IIIa antagonists, the accurate use of platelet function tests to define safe and efficacious drug dosing, the adjunctive use of additional anti-thrombotic agents, and the optimal timing of upstream therapy before diagnostic cardiac catheterization and revascularization.

Defining the optimal pharmacotherapy of non-ST-segment elevation (NSTE) acute coronary syndromes (ACS): a rapidly moving target.

Acute coronary syndromes (ACS) represent a spectrum of disease, including unstable angina, non ST-elevation myocardial infarction, and ST-elevation myocardial infarction. In patients with cardiovascular disease, ACS represents the most common diagnosis for hospital admission, accounting for nearly 1.5 million hospital admissions in 1999. Similarly, although improvements in medical therapy have resulted in a dramatic decline in mortality from acute myocardial infarction (MI) over the last four decades, MI remains the most common cause of in-hospital death in industrialized nations. The approach to managing patients with acute coronary syndromes has evolved dramatically over the past decade and, in many respects, represents a rapidly moving target in light of recent advances in pharmacotherapy and catheter-based revascularization. A number of recently-published studies, including the TACTICS Trial, the ADMIRAL Trial, and the TARGET Trial, provide novel information about the relative merits of pharmacologic therapy and invasive intervention, A common theme from these studies is that there is a growing consensus among cardiologists that combination therapy with these two modalities may actually provide the best clinical outcomes in ACS patients.

A comparison of ON-PUMP vs OFF-PUMP coronary artery bypass surgery among low, intermediate, and high-risk patients: the Hartford Hospital experience.

BACKGROUND: Off-pump coronary artery bypass (OP-CAB) graft surgery is being used with increasing frequency. This study was designed to compare OP-CAB outcomes with conventional surgical revascularization using cardiopulmonary bypass (CPB) in patients with varying risk categories at a high-volume center. METHODS AND RESULTS: Between 1/1/1999 and 1/31/2001, bypass surgery was performed on 1,312 patients, including 348 OP-CAB cases and 964 CPB cases. Compared to CPB cases, OP-CAB patients were more likely to be female and had a lower incidence of three vessel coronary artery disease, prior percutaneous intervention, and prior bypass surgery. Postoperatively, OP-CAB patients had a lower incidence of renal failure and prolonged ventilatory support, as well as a lower composite endpoint of inhospital mortality, perioperative myocardial infarction, cerebrovascular accident, and/or renal failure. In addition, OP-CAB patients required fewer transfusions and had a shorter total length of hospital stay. In general, morbidity and mortality increased in both OP-CAB and CPB groups with increasing Parsonnet score. CONCLUSIONS: OP-CAB surgery is a safe and effective alternative to conventional coronary artery bypass graft (CABG) surgery, with a lower incidence of major in-hospital adverse clinical events and a decreased requirement for medical resources. Adverse OP-CAB outcomes correlate well with pre-operative Parsonnet Score.

Suture closure of the femoral arteriotomy following invasive cardiac procedures: a detailed analysis of efficacy, complications, and the impact of early ambulation in 1,200 consecutive, unselected cases.

The purpose of this study was to assess the efficacy and safety of using a percutaneous suture device to close femoral arteriotomies following invasive cardiac procedures. All patients presenting for invasive cardiac procedures performed from the femoral artery were considered for suture closure. Patients were carefully assessed for access site complications, oozing, and the impact of suture closure on the safety of early ambulation. Clinical follow-up at 3-6 months was performed to assess for late complications. Femoral artery suture closures were performed in 1,200 consecutive cases in 1,097 patients. In 12.8% of cases, the patients ambulated within 1 hr. The success rate was 91.2% and the complication rate was 3.4%. Complications included the development of a hematoma (2.1%), the need for vascular surgery (0.6%), retroperitoneal hemorrhage (0.3%), blood transfusion (0.7%), local infection (0.5%), and pseudoaneurysm formation (0.1%). Factors found to be independently predictive of procedural failure were an age > 70 years, an ACT > 300 sec, left femoral artery access, and the performance of primary angioplasty. Follow-up at 3-6 months revealed no major hemorrhagic complications. We conclude that percutaneous suture closure effectively achieves femoral artery hemostasis in patients undergoing invasive cardiac procedures. The technique permits early ambulation and is associated with a relatively low incidence of complication.

Heart rate-lowering calcium antagonists in hypertensive post-myocardial infarction patients.

OBJECTIVES: To analyse effects of a heart rate-lowering calcium antagonist in hypertensive post-myocardial infarction patients. DESIGN AND METHODS: From three large, randomized, placebo-controlled, secondary prevention trials investigating verapamil or diltiazem (the first and second Danish Verapamil Infarction Trials and the Multicentre Diltiazem Post-Infarction Trial) data from a total of 1,325 hypertensive post-myocardial infarction patients (drugs = 667, placebo = 658) were pooled to assess effect of blinded therapy on mortality and event rates. RESULTS: Treatment with heart rate-lowering calcium antagonists was associated with significant reduction in event rates [21.4 versus 27.4%; risk ratio (RR) = 0.76, confidence interval (CI) = 0.61 -0.95, P= 0.013]. Mortality rates in the treatment group were 15.1 versus 17.5% in the control group (RR = 0.87, CI = 0.66-1.13, P= 0.296). Among the subset of 964 hypertensive patients without pulmonary congestion, there was some reduction in mortality rate (11.3 versus 15.3% in the control group; RR = 0.72, P= 0.066) and significant reduction in event rates (18 versus 24.4% for control group; RR = 0.70, P= 0.011). In patients with pulmonary congestion and hypertension, however, calcium antagonists were associated with a 25% increase in mortality (RR = 1.25, P= 0.339), while event rate RR was 1.00. After an adjustment for significant covariates, RR for mortality in treatment versus control groups was 0.76 (P= 0.159). For event rates, RR was 0.74 (P= 0.057). CONCLUSIONS: Heart rate-lowering calcium antagonists decrease event rates in hypertensive post-myocardial infarction patients, but only in those without pulmonary congestion.

Heart rate-lowering and -regulating effects of once-daily sustained-release diltiazem.

BACKGROUND: Epidemiologic evidence suggests that an elevated heart rate (HR) is an adverse and independent prognostic factor in arterial hypertension and other cardiovascular diseases. Although diltiazem is characterized as an HR-lowering calcium antagonist, no studies have quantified the magnitude of HR changes in patients with angina or hypertension. HYPOTHESIS: The study was undertaken to explore the magnitude of proportional HR reduction at varying levels of resting HR with the sustained-release formulation of diltiazem (SR diltiazem) at the usual clinical doses of 200 or 300 mg once daily. METHODS: This meta-analysis was conducted on six comparative double-blind studies including 771 patients with angina or hypertension in which SR diltiazem 200-300 mg once daily was compared either with placebo or with other agents known not to influence HR (angiotensin-converting enzyme inhibitors, diuretics). Sustained-release diltiazem decreases elevated baseline HR, with an increasing effect at higher initial rates. RESULTS: Multiple comparisons by baseline HR category showed a significant difference between both groups for baseline HR of 74-84 beats/min and > or = 85 beats/min (p = 0.001). Sustained-release diltiazem had no significant HR-decreasing effect on baseline HR < or =74 beats/min but appears to have a genuine regulating effect on HR: it reduces tachycardia without inducing excessive bradycardia. These findings are in contrast to those with dihydropyridine calcium antagonists, which tend to increase HR and have been associated with an adverse outcome in acute cardiovascular conditions. At the same time, there is evidence to suggest that HR-lowering calcium-channel blockers decrease cardiovascular event rates following myocardial infarction. CONCLUSION: When calcium antagonists are indicated for use in patients with angina or hypertension, an HR-lowering agent, that is, diltiazem rather than dihydropyridine, should be recommended.

Non-Q-wave myocardial infarction following thrombolytic therapy: a comparison of outcomes in patients randomized to invasive or conservative post-infarct assessment strategies in the Veterans Affairs non-Q-wave Infarction Strategies In-Hospital (VANQWISH) Trial.

OBJECTIVES: We wished to determine the effect of post-infarct management strategy on event rates (death or recurrent nonfatal myocardial infarction [MI]) in patients who evolved non-Q-wave MI (NQMI) following thrombolytic therapy. BACKGROUND: Patients who evolve NQMI following thrombolytic therapy are often considered to be at high risk and are frequently managed with routine early invasive testing despite a lack of data supporting improved outcome. METHODS: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study included 115 patients who evolved NQMI following thrombolytic therapy. We compared the event rates in patients randomized to routine early coronary angiography with those in patients randomized to a conservative strategy of noninvasive functional assessment, with angiography reserved for patients with spontaneous or induced ischemia. RESULTS: During an average follow-up of 23 months, 19 of 58 patients (33%) randomized to the invasive management strategy died or suffered recurrent nonfatal MI, compared with 11 of 57 patients (19%) randomized to the conservative strategy (p = 0.152). Equivalent numbers of patients were subjected to revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass graft). There were more deaths in the invasive management group than in the conservative management group (11 vs. 2). Excess deaths could not be attributed to periprocedural mortality. CONCLUSIONS: Overall event rates (death or recurrent nonfatal MI) are comparable with conservative and invasive strategies in patients who evolve NQMI following thrombolytic therapy. Mortality rate in patients managed conservatively is low (3.5%), and routine invasive management may be associated with an increased risk of death.

Early invasive versus ischaemia-guided strategies in the management of non-Q wave myocardial infarction patients with and without prior myocardial infarction; results of Veterans Affairs Non-Q Wave Infarction Strategies in Hospital (VANQWISH) trial.

AIMS: To compare the role of early invasive vs conservative management strategies in treating patients with non-Q wave myocardial infarction with or without a prior myocardial infarction. BACKGROUND: In patients recovering from non-Q wave myocardial infarction, the prognosis among patients with a first non-Q wave myocardial infarction is significantly better than in patients with a prior myocardial infarction, yet physicians often adopt an early invasive strategy to treat patients with a first non-Q wave myocardial infarction. METHODS: Non-Q wave myocardial infarction patients enrolled in the VANQWISH trial with a history of prior myocardial infarction were compared to those with a first non-Q wave myocardial infarction, for the trial primary end-point of death or myocardial infarction at 1 and 12 months, as well as for the initial randomized treatment strategy. RESULTS: Of the 920 non-Q wave myocardial infarction patients, 396 had a history of prior myocardial infarction and 524 did not. Patients with a history of prior myocardial infarction were older and had a higher incidence of multiple high-risk baseline characteristics than those with a first non-Q wave myocardial infarction. Compared to the group with a first myocardial infarction, the prior myocardial infarction group suffered more events at both 1 month (11% vs 6%, P=0.007) and at 12 months (29% vs 16%, P<0.001). This difference in outcome remained significant even after adjusting for confounding variables (P<0.0001 at 12 months). Among the non-Q wave myocardial infarction patients with a prior myocardial infarction, the frequency of death or recurrent myocardial infarction was similar in both invasive and conservative groups during the first year of follow-up. Among the first non-Q wave myocardial infarction group, those assigned to the conservative strategy had significantly fewer events (3% vs 9%, P=0.009 at 1 month; 12% vs 20%, P=0.016 at 12 months) and mortality (1% vs 5%, P=0.012 at one month; 5% vs 11%, P=0.009 at 12 months) than those assigned to early invasive strategy. CONCLUSION: A history of prior myocardial infarction identifies a moderately high-risk subset of non-Q wave myocardial infarction patients who display similar long-term outcomes regardless of the strategy assignment; however, patients with a first non-Q wave myocardial infarction may fare better with a conservative or ischaemia-guided approach during the first post infarction year.

Raising low levels of high-density lipoprotein cholesterol is an important target of therapy.

Recent clinical trials in patients with coronary heart disease indicate, for the very first time, that increasing low levels of high-density lipoprotein (HDL) cholesterol significantly reduces the cumulative occurrence of cardiovascular and cerebrovascular events in patients whose only lipid abnormality was low HDL with normal levels of low-density lipoprotein (LDL) cholesterol and triglycerides. These data provide a compelling scientific basis for a more targeted and segmental approach to managing patients with dyslipidemia, where decreasing elevated levels of LDL cholesterol and increasing low levels of HDL cholesterol should comprise dual targets of pharmacotherapy.

Long-term effects of diltiazem and verapamil on mortality and cardiac events in non-Q-wave acute myocardial infarction without pulmonary congestion: post hoc subset analysis of the multicenter diltiazem postinfarction trial and the second danish verapamil infarction trial studies.

The main objective of this retrospective analysis was to evaluate the long-term effect of the heart rate-lowering calcium antagonists verapamil and diltiazem on the incidence of combined cardiac events and all-cause mortality in patients who had experienced a non-Q-wave acute myocardial infarction (AMI), but who did not also have pulmonary congestion. In addition, factors having an independent association with these 2 outcomes were identified. Of 817 non-Q-wave patients, 81 (9.9%) died during 12 to 52 months of follow-up. The unadjusted mortality rate was 42% lower in patients randomized to calcium antagonist therapy than placebo (7.2% vs 12.4%, p = 0.010). Non-Q-wave patients who died during follow-up were older than patients who survived (62 vs 58 years, p = 0.001). Other factors found to have an independent association with all-cause mortality included diuretic use (RR 2.79), diabetes mellitus (RR 2.86), and New York Heart Association class >I (RR 1.73). The covariate adjusted all-cause mortality risk ratio associated with randomization to calcium antagonist therapy was 0.65 (95% confidence interval [0.40 to 1.05, p = 0.079]). Overall, 153 patients (18.7%) died or had nonfatal reinfarction. The unadjusted combined event rate was 31% lower in patients randomized to calcium antagonist therapy than to placebo (15.2% vs 21.9%, p <0.006). Factors found to have an independent association with cardiac events included age, diabetes (RR 2.82), diuretic use (RR 2.04), and previous AMI (RR 1. 71). In addition, randomization to the calcium antagonist group had a significant independent association with reduced cardiac events (p = 0.031). The covariate adjusted event rate RR associated with randomization to the calcium antagonist group was 0.69 (95% confidence interval [0.49 to 0.97]). In conclusion, the heart rate-lowering calcium antagonists diltiazem and verapamil may play an important role in reducing long-term mortality and reinfarction in non-Q-wave AMI without pulmonary congestion.

Diltiazem in acute myocardial infarction treated with thrombolytic agents: a randomised placebo-controlled trial. Incomplete Infarction Trial of European Research Collaborators Evaluating Prognosis post-Thrombolysis (INTERCEPT)

BACKGROUND: Diltiazem reduces non-fatal reinfarction and refractory ischaemia after non-Q-wave myocardial infarction, an acute coronary syndrome similar to the incomplete infarction that occurs after successful reperfusion. We postulated that this agent would reduce cardiac events in patients after acute myocardial infarction treated initially with thrombolytic agents-a clinical application previously unexplored with heart-rate-lowering calcium antagonists. METHODS: A prospective, randomised, double-blind, sequential trial was done in 874 patients with acute myocardial infarction, but without congestive heart failure, who first received thrombolytic agents. Patients received either 300 mg oral diltiazem once daily, or placebo, initiated within 36-96 h of infarct onset, and given for up to 6 months. The trial primary endpoint was the cumulative first event rate of cardiac death, non-fatal reinfarction, or refractory ischaemia. Additional prespecified endpoints included several composites of non-fatal cardiac events (non-fatal reinfarction combined with refractory ischaemia, all recurrent ischaemia, or the need for myocardial revascularisation). The diagnosis of ischaemia, whether refractory or recurrent, and the need for myocardial revascularisation, was always based on objective electrocardiographical evidence of ischaemia, either at rest or on exertion. RESULTS: For the trial primary endpoint, 131 events occurred in the 444 placebo patients and 97 events in the 430 diltiazem patients (hazard ratio 0.79; 95% CI, 0.61-1.02; p=0.07). For non-fatal cardiac events, diltiazem treatment was associated with a relative decrease (0.76; 0.58-1.00) in the combined event rate of non-fatal reinfarction and refractory ischaemia. There was a similar decrease in the composite non-fatal endpoints of non-fatal reinfarction combined with all recurrent ischaemia (0.80; 0.64-1.00) and non-fatal reinfarction combined with the need for myocardial revascularisation (0.67; 0.46-0.96). The need for myocardial revascularisation alone was significantly reduced by 42% (0.61; 0.39-0.96). No major safety issues were encountered. CONCLUSIONS: Diltiazem did not reduce the cumulative occurrence of cardiac death, non-fatal reinfarction, or refractory ischaemia during a 6-month follow-up, but did reduce all composite endpoints of non-fatal cardiac events, especially the need for myocardial revascularisation.

High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High--Density Lipoprotein Intervention Trial.

The Framingham Heart Study found that high-density lipoprotein cholesterol (HDL-C) was the most potent lipid predictor of coronary artery disease risk in men and women >49 years of age. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), in which subjects were randomized to treatment with lovastatin or placebo, also reported a striking benefit of treatment, particularly in patients with HDL-C < or =35 mg/dL at baseline. Treatment with lovastatin was associated with a remarkable 45% reduction in events for this group. The Veterans Affairs HDL Intervention Trial (VA-HIT) randomized subjects to gemfibrozil or placebo. A high proportion of enrolled subjects with low HDL-C also had characteristics of the dysmetabolic syndrome. HDL-C likewise increased by 6% on treatment, total cholesterol was reduced by 4% and triglycerides by 31%. There was no change in low-density lipoprotein cholesterol (LDL-C) levels. These changes in lipid were associated with a cumulative 22% reduction in the trial primary endpoint of all-cause mortality and nonfatal myocardial infarction (MI). Additionally, significant reductions in secondary endpoints including death from coronary artery disease, nonfatal MI, stroke, transient ischemic attack, and carotid endarterectomy were associated with the increase in HDL-C. In VA-HIT, for every 1% increase in HDL-C, there was a 3% reduction in death or MI, a therapeutic benefit that eclipses the benefit associated with LDL-C reduction.