Events In High-risk Patients Research Articles

Clinical evidence from ONTARGET: the value of an angiotensin II receptor blocker and an angiotensin-converting enzyme inhibitor

The Heart Outcomes Prevention Evaluation study established the angiotensin-converting enzyme inhibitor ramipril, versus placebo, for prevention of cardiovascular events in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was later conducted in similar high-risk patients using multifactorial treatment to control hypertension, platelet aggregation, and dyslipidemia, while comparing ramipril, telmisartan, or their combination, without placebo. In ONTARGET, the first angiotensin II receptor blocker-based study to be performed in a broader population of patients without congestive heart failure and/or left ventricular hypertrophy/dysfunction, telmisartan provided cardiovascular protection that was noninferior to ramipril. However, greater blockade of the renin-angiotensin system, using their combination, was not superior to ramipril alone. Telmisartan was better tolerated than ramipril in this high-risk population: notably, the incidence of cough and angioedema was significantly lower with telmisartan alone. Thus, telmisartan provides comparable efficacy to ramipril with less adverse events, which may encourage patient compliance.

Bisoprolol and Fluvastatin for the Reduction of Perioperative Cardiac Mortality and Myocardial Infarction in Intermediate-Risk Patients Undergoing Noncardiovascular Surgery

This study evaluated the effectiveness and safety of beta-blockers and statins for the prevention of perioperative cardiovascular events in intermediate-risk patients undergoing noncardiovascular surgery. Beta-blockers and statins reduce perioperative cardiac events in high-risk patients undergoing vascular surgery by restoring the myocardial oxygen supply/demand balance and/or stabilizing coronary plaques. However, their effects in intermediate-risk patients remained ill-defined. In this randomized open-label 2 x 2 factorial design trial 1066 intermediate cardiac risk patients were assigned to bisoprolol, fluvastatin, combination treatment, or control therapy before surgery (median: 34 days). Intermediate risk was defined by an estimated risk of perioperative cardiac death and myocardial infarction (MI) of 1% to 6%, using clinical data and type of surgery. Starting dose of bisoprolol was 2.5 mg daily, titrated to a perioperative heart rate of 50 to 70 beats per minute. Fluvastatin was prescribed in a fixed dose of 80 mg. The primary end point was the composite of 30-day cardiac death and MI. This study is registered in the ISRCTN registry and has the ID number ISRCTN47637497. Patients randomized to bisoprolol (N = 533) had a lower incidence of perioperative cardiac death and nonfatal MI than those randomized to bisoprolol-control (2.1% vs. 6.0% events; hazard ratios: 0.34; 95% confidence intervals: 0.17-0.67; P = 0.002). Patients randomized to fluvastatin experienced a lower incidence of the end point than those randomized to fluvastatin-control therapy (3.2% vs. 4.9% events; hazard ratios: 0.65; 95% confidence intervals: 0.35-1.10), but statistical significance was not reached (P = 0.17). Bisoprolol was associated with a significant reduction of 30-day cardiac death and nonfatal MI, while fluvastatin showed a trend for improved outcome.

Main results and clinical interpretations from the TRANSCEND study

Angiotensin-converting enzyme (ACE) inhibitors are useful drugs for preventing cardiovascular disease and death in patients at risk. However, a significant proportion of patients experience side effects, mainly cough or less frequently angioedema, when treated with ACE inhibitors. Angiotensin receptor blockers (ARBs) are also useful drugs for treatment of hypertension, diabetic nephropathy and patients with left ventricular dysfunction or cardiac failure who are intolerant to ACE inhibitors. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) study examined the effect of a long-acting ARB, telmisartan, on cardiovascular events in a group of patients at high-risk for cardiovascular disease who were intolerant to ACE inhibitors. Five thousand nine hundred twenty-six patients with known intolerance to ACE inhibitors were randomized to telmisartan or placebo added to current treatments. The primary composite endpoint, a sum of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to heart failure was nonsignificantly reduced in telmisartan-treated patients with respect to placebo (15.7 vs. 17%; relative risk reduction 8%). The key secondary endpoint (the primary endpoint excluding heart failure hospitalization) was reduced in telmisartan-treated patients by 13% (13 vs. 14.8%; P = 0.046). In conclusion, telmisartan reduces cardiovascular events in high-risk patients with the exception of heart failure hospitalization and can be considered as the first-line therapy in those intolerant to ACE inhibitors.

Percutaneous closure of left atrial appendage to prevent embolic events in high‐risk patients with chronic atrial fibrillation

Percutaneous closure of the left atrial appendage (LAA) is a novel alternative for the treatment of patients with atrial fibrillation (AF) and with a high risk of stroke who are not eligible for long-term anticoagulation therapy. The aim of this study was to asses the safety, feasibility, and long-term efficacy of this procedure. From July 2004 to June 2007, 20 patients (13 male, mean age 69 +/- 8 years) with non-valvular AF (NV-AF) underwent LAA percutaneous closure using the PLAATO system, implanted through a transeptal access. All patients had contraindications to anticoagulant therapy and were at high risk for cardioembolic stroke (mean CHADS(2) score 3 +/- 1.2). A trans-thoracic echocardiogram was performed at 1, 3, and every 6 months after the procedure, whereas a trans-oesophageal echocardiogram (TOE) was scheduled at 6 months. After 24 months, a phone interview was obtained. All procedures were successfully performed in 18 patients. In two patients, LAA closure was not feasible for the presence of a multilobed LAA. Two patients underwent percutaneous closure of patent foramen ovale in the same session. In one patient, the procedure was complicated by cardiac perforation with pericardial effusion, treated with pericardiocentesis. At a mean follow up of 40 +/- 10 months, no embolic events occurred. One patient died, after 36 months, for gastric cancer. TOE examination showed the complete exclusion of the LAA in all patients. Percutaneous closure of LAA is safe and efficacious to prevent stroke in patients with NV-AF at high risk for cardioembolic events, with contraindications to anticoagulant therapy.

New paradigms of care for STEMI focusing on mortality and attributable death analysis: what do device and drug trials teach us?

In patients with acute coronary syndromes, ST-segment elevation myocardial infarction (STEMI), and in those undergoing percutaneous coronary intervention (PCI), major bleeding has been shown to be a powerful independent determinant of mortality, at least as important as MI or re-infarction. Treatment with bivalirudin compared with heparin and a GP IIb/IIIa inhibitor results in a significant reduction in 30-day major bleeding, thrombocytopaenia and transfusions, with similar rates of ischaemic events in high-risk patients with STEMI undergoing primary PCI. Furthermore, bivalirudin monotherapy resulted in significant 31 and 43% reductions in rates of all-cause and cardiac mortality (absolute 1.4 and 1.7% reductions) at 1 year, with non-significantly different rates of re-infarction and stent thrombosis. The prevention of haemorrhagic complications after primary PCI in STEMI results in improved early and late survival. Optimal drug selection and technique to minimize bleeding are essential to enhance outcomes for patients undergoing interventional therapies.

ONTARGET: Use of ramipril, telmisartan, or both in patients with high cardiovascular risks

Introduction: Angiotensin-converting enzyme (ACE) inhibitors have been shown to prevent cardiovascular events in high-risk patients in multiple studies. Among numerous trials, the use of ACE inhibitors was investigated for patients with left ventricular dysfunction [1], acute myocardial infarction (MI) [2], previous cardiovascular disease (CVD) or high-risk diabetes [3,4], and heart failure [5,6]. Additionally, the benefi t of angiotensin receptor blockers (ARBs) in high-risk patients with heart failure, MI, and left ventricular dysfunction was demonstrated in multiple studies [7–9]. However, ARB’s role in reducing the CVD events for high-risk patients without heart failure is not well defi ned. The renin-angiotensin system (RAS) plays an important role in hypertension, cardiovascular, and renal diseases. Because inhibition of RAS with ACE inhibitors or ARBs is usually incomplete due to various escape mechanisms [10,11], dual blockade of RAS with ACE inhibitors and ARBs appears to be an attractive medical treatment option. Combination therapy is supported by the recent meta-analysis in which combination therapy reduced proteinuria and blood pressure compared with monotherapy [12]; however, the fact that combination therapy leads to better clinical outcomes, such as reducing the CVD events, still remains controversial. Recent evidence from large trials and meta-analyses showed no additional clinical benefi t with combination therapy [13,14]. We reviewed the article on the recently published ONTARGET trial in which the effi cacy of telmisartan with or without ramipril in high-risk patients was investigated.

Plasma N-Terminal Prohormone Brain Natriuretic Peptide as a Marker for Postoperative Cardiac Events in High-Risk Patients Undergoing Noncardiac Surgery

This study considered if N-terminal prohormone brain natriuretic peptide (NT-proBNP) is associated with increased risk for postoperative cardiac events in high-risk patients undergoing noncardiac surgery. In addition, this report describes how levels of NT-proBNP are affected by noncardiac surgery. The study design was a prospective cohort study that enrolled 83 patients age > or =50 years with > or =1 risk factor for coronary artery disease having intermediate or high-risk noncardiac surgery. NT-proBNP levels were measured preoperatively and on postoperative days 1 and 3. During the month following surgery, 25 patients (33%) had a combined 37 postoperative cardiac events including 15 episodes of heart failure (20%), 12 episodes of new dysrhythmia (16%), 7 myocardial infarctions (9%), and 3 cardiac arrests (4%). Preoperative NT-proBNP level > or =457 pg/ml was significantly associated with occurrence of a postoperative cardiac event (odds ratio 10.5, 95% confidence interval 1.9 to 56.6, p = 0.006). After surgery, 64 of 72 patients (89%) had an increase in NT-proBNP from their preoperative level. In conclusion, this study determined there was a significant association between elevated preoperative NT-proBNP and occurrence of a postoperative cardiac event. In addition, increased NT-proBNP after noncardiac surgery is not uncommon even in the absence of clinically identifiable heart failure.

Vitamin E and prevention of heart disease in high-risk patients.

Several observational studies have suggested that high intake of vitamin E may slow the development and progression of atherosclerosis. Some clinical trials also reported beneficial effects of vitamin E supplementation in the secondary prevention of cardiovascular events. However, results of recent large, multicenter clinical trials reported that vitamin E supplementation was not effective in reducing the incidence of cardiovascular events in high-risk patients.

Reversible Posterior Leukoencephalopathy Syndrome in Sickle-Cell Anemia

A 10-year-old African American girl with sickle-cell anemia developed headaches and seizures associated with hypertension during hospitalization for a pulmonary abscess. Hypertension developed after multiple transfusions, associated with abnormally high hematocrit and headache. Magnetic resonance imaging was consistent with posterior leukoencephalopathy. Neurologic signs, hypertension, and high hematocrit resolved after erythrocytapheresis. Magnetic resonance imaging, 1 month after the episode, produced normal results. Because reversible posterior leukoencephalopathy syndrome was only described in sickle-cell anemia during severe acute chest syndrome, this report documents that milder illness can be associated with reversible posterior leukoencephalopathy syndrome in sickle-cell anemia, and also highlights subtle signs that may herald serious neurologic events in high-risk patients. Examination of the pathophysiology of reversible posterior leukoencephalopathy syndrome in the context of sickle-cell anemia suggests that patients with sickle-cell anemia and subtle neurologic signs should be treated with high vigilance.

High-molecular-weight adiponectin does not predict cardiovascular events in patients with type 2 diabetes

Low circulating high-molecular-weight (HMW) adiponectin might be associated with increased cardiovascular risk. This study aimed to investigate the relationship between HMW adiponectin and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) with an adverse cardiovascular risk profile. The investigation took place in a specialized outpatient clinic for metabolic diseases and included 147 patients with T2DM following a cross-sectional and a prospective study protocol. Ninety patients had macrovascular disease at baseline defined as preexisting coronary artery disease, previous stroke, or peripheral artery disease. HMW adiponectin measured by enzyme-linked immunosorbent assay (Fujirebio, Tokyo, Japan) and routine clinical parameters were determined in all patients at baseline. The occurrence of new cardiovascular events (myocardial infarction, stroke, and all-cause mortality) during the follow-up period was evaluated. No significant correlations between traditional cardiovascular risk markers and HMW adiponectin could be detected. HMW adiponectin did not differ between subjects with and without macrovascular disease at baseline (3.5 [interquartile range [IQR]: 2.2-5.7] mg/L vs 4.0 [IQR: 2.5-7.1] mg/L). During a follow-up of 19.3 (IQR: 16-25) months, 61 endpoints (41 myocardial infarctions, 10 strokes, and 10 deaths) were observed. A 1-standard-deviation increment of log-transformed HMW adiponectin was not significantly associated with the occurrence of cardiovascular events (Adjusted hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.58-1.54; P = 0.835). In conclusion, HMW adiponectin was not related to present macrovascular disease and is not associated with future cardiovascular events in high-risk patients with T2DM. It is unlikely that HMW adiponectin has significant vasoprotective effects in these patients.

Thiazolidinediones: effects on the development and progression of type 2 diabetes and associated vascular complications

In addition to reducing hyperglycaemia, the metabolic actions of TZDs (pioglitazone and rosiglitazone) in theory might improve the prognosis of patients with type 2 diabetes. However, it appears from recent data that pioglitazone and rosiglitazone have different cardiovascular risk profiles. The scope of this paper is to examine the benefits and risks of pioglitazone and rosiglitazone. Three large clinical studies (DREAM, and ADOPT with rosiglitazone; PROactive with pioglitazone) have recently been reported. A lower annual rate of decline of ss-cell function observed with rosiglitazone in the ADOPT study, compared with metformin and glyburide (glibenclamide), along with a reduced progression to insulin use seen with pioglitazone in the PROactive study, provides evidence that TZDs are effective in treating progressive hyperglycaemia. In PROactive, although the primary endpoint was not met, pioglitazone was associated with a reduction in a secondary composite endpoint of clinical cardiovascular events in high-risk patients with existing macrovascular disease who were already receiving other glycaemic and cardiovascular medications. Further evidence supporting an anti-atherogenic effect of pioglitazone was gained from the PERISCOPE study of carotid intima-media thickness. Recent controversy concerning a possible increased risk of myocardial infarction associated with rosiglitazone has fuelled uncertainty about the risk-benefit profile of this agent. In 2008, an update of an American Diabetes Association-European Association for the Study of Diabetes consensus statement on initiation and adjustment of therapy in patients with type 2 diabetes advised clinicians against using rosiglitazone. Skeletal fractures have recently emerged as a side effect of both TZDs. Available data suggest that cardiovascular benefits observed with pioglitazone might not be a class effect of TZDs.

Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

A Review of Lipid Management in Primary and Secondary Prevention

Lipid management in primary and secondary prevention reduces cardiovascular morbidity and mortality. Lowering of low-density lipoprotein cholesterol (LDL-C) levels with statins remains the primary goal of therapy. For secondary prevention patients, those with coronary heart disease (CHD) or CHD risk equivalents, intensive LDL-C lowering is recommended, although the precise target value is still debated. For primary prevention, reduction in LDL-C levels is based on patient risk for CHD. In clinical outcome trials to date, statins benefit those who are at moderate to high risk and appear to have less clinical benefit for those at low risk. Yet despite aggressive LDL-C management with statins, there remains a residual risk for CHD events in high-risk patients. Secondary targets have been proposed to decrease this risk, including non-high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and apolipoprotein B, as well as other emerging targets, including LDL particle number and lipoprotein(a). In many high-risk patients, statin monotherapy is unlikely to achieve goals, and combination therapy with other agents is a safe, effective, and optimal therapeutic approach.

Abstract 3033: Predictive Factors of Target Vessel Revascularization after Drug-eluting Stent Implantation in the NHLBI Dynamic Registry

Drug-eluting stents (DES) reduce the risk of restenosis, however, the benefit may not be consistent or result in fewer repeat interventions in all patient and lesion subsets. We sought to identify the clinical presentation and predictive factors of target vessel revascularization (TVR) in unselected patients treated with DES. Patients with all lesions treated with a DES in the NHLBI Dynamic Registry were analyzed. Included were 2790 patients with 3532 target lesions. All patients were followed prospectively for at least one-year. Target vessel revascularization was defined as any repeat percutaneous coronary intervention involving the target vessel. Baseline characteristics of patients with and without subsequent TVR were compared and independent predictors of TVR were determined by multivariate analysis. Clinically driven TVR occurred in 131 patients (4.7%) and 170 lesions (4.8%). The indication for first TVR was myocardial infarction (n = 29) 22.1%, unstable angina (n = 79) 60.3%, stable angina (n = 21) 16%, other (n = 2) 1.5%. Among patients with TVR the rate of stent thrombosis at 1 year was (n = 17) 13% and 15 of these patients had TVR within 3 days of ST. Several predictors of TVR were identified (Table ) the strongest being diabetes, prior in-stent restenosis, and attempted graft lesion. Stent type, sirolimus vs. other (adjusted OR 0.96, CI 0.36 –2.57) and paclitaxel vs. other (adjusted OR 0.75, CI 0.27–2.10), was not associated with TVR. Although the rate of TVR is low in patients treated with DES, certain patient and lesion subsets predict a higher risk of TVR. Of concern, unlike historical bare metal stent restenosis, TVR events were mainly related to acute coronary syndromes. These observations highlight the need for new stent technology to prevent restenosis and stent thrombosis and more aggressive medical therapy to prevent ischemic events in high risk patients. Adjusted Odds Ratio Model For Target Vessel Revascularization

Increasing Carotid Plaque Echolucency is Predictive of Cardiovascular Events in High-Risk Patients

Carotid plaque echolucency seen at ultrasonography (US) is a potential indicator of plaque instability and may help identify patients at risk for major adverse cardiovascular events (MACEs). The authors performed this study to determine whether decreasing gray-scale median (GSM) levels at repeat carotid US examinations are associated with future MACEs. The study was approved by the institutional ethics committee and all patients provided informed consent. The authors prospectively studied 574 patients with carotid plaques of at least 30% from a group of 1268 consecutive patients who were initially asymptomatic with respect to carotid disease. GSM levels were determined with carotid US at baseline and after a median of 7.5 months (range, 6-9 months), and the mean change of the GSM was calculated. Patients were then followed up clinically for a median of 3.2 years for the occurrence of composite MACE. During the initial period, the median change in carotid GSM was 2.9 (interquartile range [IQR], -6.9 to 11.0). Of 574 study participants, 230 (40%) showed a reduction of GSM levels and 344 (60%) showed an increase. MACEs were observed in 177 (31%) of the 574 patients. Adjusted hazard ratios for the lowest quartile (GSM change less than -6.9), the second quartile (GSM change between -6.9 and 2.9), and the third quartile (GSM change between 3.0 and 11.0) were 1.71 (95% confidence interval [CI]: 1.09, 2.66), 1.36 (95% CI: 0.86, 2.16), and 1.22 (95% CI: 0.77, 1.95), respectively, compared with the highest quartile (GSM change greater than 11.0) (P = .018). Increasing echolucency of carotid artery plaques within a 6- to 9-month interval is predictive of midterm clinical adverse events of atherosclerosis.

Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity

The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. Optimization of this series has led to the discovery of 4 (SCH 530348), a potent, oral antiplatelet agent that is currently undergoing Phase-III clinical trials for acute coronary syndrome (unstable angina/non-ST segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients.

Data Suggest Approach to Hypertension Management Should Change

New data challenge the current guidelines for management of hypertension, which recommend initiating treatment with a diuretic and suggest monotherapy as the starting point of treatment. The ACCOMPLISH trial showed that a single-pill combination of an angiotensin-converting enzyme inhibitor and a calcium channel blocker led to excellent blood pressure control and significantly reduced the risk of cardiovascular events in high-risk patients.

Role of Antiplatelet Agents in the Primary and Secondary Prevention of Atherothrombotic Events in High Risk-Patients

Atherothrombosis describes the superimposition of a thrombus on a ruptured atherosclerotic plaque, and is the primary cause of acute ischemic events. Atherothrombosis is a generalized and progressive process with an inflammatory component. Patients with disease in one vascular bed are at risk of disease in another, a concept known as "cross-risk." Platelet adhesion, activation, and aggregation in the final stage of atherothrombosis are ultimately responsible for arterial occlusion and consequent ischemia. Therefore, antiplatelet therapy is an effective treatment choice for secondary prevention. Clopidogrel, an adenosine diphosphate receptor antagonist, given alone or in combination with aspirin, may benefit secondary prevention of ischemic events. Current treatment guidelines suggest the use of a combination of these two agents for secondary prevention where appropriate. However, data conflict regarding the efficacy of antiplatelet therapy for primary prevention. A recent meta-analysis demonstrated that aspirin significantly reduces the risk of first myocardial infarction in both men and women. The recent Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, which evaluated the effects of clopidogrel plus aspirin compared with aspirin alone, seems to support the use of dual antiplatelet therapy in secondary prevention, but suggests that it may not be more effective than aspirin alone in primary prevention.

Dual Therapy With Statins and Antioxidants Is Superior to Statins Alone in Decreasing the Risk of Cardiovascular Disease in a Subgroup of Middle-Aged Individuals With Both Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Diabetes Mellitus (DM) is associated with a state of increased oxidative stress.1 Paradoxically, however, antioxidants have not been found to provide CVD benefit to DM individuals in several prospective clinical trials.2–11 However, the inability to demonstrate benefit may have been attributable to inadequate patient selection as antioxidants may only benefit those with particularly high levels of oxidative stress.12 A polymorphism in the Haptoglobin (Hp) gene, an antioxidant protein, appears to permit identification of individuals with high oxidative stress and who may benefit from antioxidant therapy.13 There exists 2 classes of alleles at the Hp genetic locus, 1 and 2, and the antioxidant capacity of the Hp 2 protein is inferior to the Hp 1 protein.14–18 Robust clinical data has shown that individuals homozygous for the Hp 2 allele (Hp 2-2 genotype), 40% of DM individuals, have an up to 500% increased risk of CVD.19–22 A vast amount of basic science, animal, and epidemiological data has provided the logic for targeting vitamin E administration specifically to DM individuals with the Hp 2-2 genotype.13 Most importantly we have recently reported in the ICARE study (Israel CArdiovascular events Reduction with vitamin E [ClinicalTrials.gov# NCT00220831]) a prospective randomized placebo controlled trial of vitamin E therapy in DM individuals with the Hp 2-2 genotype, that vitamin E therapy results in a 50% reduction in CVD events.22 …

Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: Results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10)

Composite end points of major adverse cardiovascular events (MACEs) are standard measures for comparing treatment in large cardiovascular outcome studies. This analysis from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive) evaluated the effects of pioglitazone on the prespecified MACE end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE1) and on 6 post hoc MACE composites (various combinations of all-cause, cardiovascular, or cardiac mortality; plus nonfatal myocardial infarction; plus nonfatal stroke; and/or acute coronary syndrome) in patients with type 2 diabetes. PROactive was a cardiovascular outcome study that randomized patients with type 2 diabetes to pioglitazone (n = 2605) or placebo (n = 2633), in addition to existing glucose-lowering and cardiovascular medications. Pioglitazone was titrated from 15 to 45 mg/d based upon tolerability. Mean follow-up was 34.5 months. At final visit, 257 (9.9%) pioglitazone-treated and 313 (11.9%) placebo-treated patients had a first event that contributed to the MACE1 end point (hazard ratio 0.82, 95% CI 0.70-0.97, P = .0201). There were statistically significant differences in favor of pioglitazone in 5 of the other MACE end points (P < .05) and a trend to benefit in the sixth (P = .052), with hazard ratios of 0.79 to 0.83. In patients with advanced type 2 diabetes at high risk for cardiovascular events, pioglitazone treatment resulted in significant risk reductions in MACE composite end points to 3 years.