Marcus Flather

Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation

BACKGROUNDnThere are wide variations between countries in the use of invasive cardiac catheterisation and revascularisation procedures for patients with acute ischaemic syndromes. We studied the relation between rates of such procedures and rates of cardiovascular death, myocardial infarction, stroke, refractory angina, and major bleeding in a prospective, registry-based study in six countries with widely varying intervention rates.nnnMETHODSn7987 consecutive patients presenting with unstable angina or suspected myocardial infarction without ST-segment elevation were recruited prospectively from 95 hospitals in six countries and followed up for 6 months.nnnFINDINGSnThe rates of all procedures were highest in patients in Brazil and the USA, intermediate in Canada and Australia, and lowest in Hungary and Poland. There were no significant differences in rates of cardiovascular death or myocardial infarction among these countries (4.7% overall [range 3.7-5.6] at 7 days; 11% overall [9-12] at 6 months). For the countries with the highest rates of invasive procedures (59%) versus the rest (21%) there was no difference in rate of cardiovascular death or myocardial infarction (adjusted odds ratio 0.88 at 7 days and 1.0 at 6 months). Rates of stroke were higher in Brazil and the USA than in the countries with lower intervention rates (adjusted odds ratio at 7 days 3.0, p=0.012; at 6 months 1.8, p=0.004) but rates of refractory angina at 7 days (0.7, p<0.001) and readmission for unstable angina at 6 months were lower (0.70, 0.63; both p<0.001). Comparison of results for hospitals without cardiac-catheterisation facilities and for those with such facilities gave adjusted odds ratios for cardiovascular death, myocardial infarction, or stroke at 6 months of 0.83 (10.6% vs 12.5%, p=0.05) and for refractory angina of 1.25 (19.3% vs 16.1%, p=0.09).nnnINTERPRETATIONnHigher rates of invasive and revascularisation procedures were associated with lower rates of refractory angina or readmission for unstable angina, no apparent reduction in cardiovascular death or myocardial infarction, but with higher rates of stroke. Randomised trials should assess the relative impact of conservative and more aggressive approaches to invasive cardiac procedures and revascularisations in patients with unstable angina.

Strengths and limitations of meta-analysis: Larger studies may be more reliable

Meta-analysis of randomized controlled trials combines information from independent studies that address a similar question to provide more reliable estimates of treatment effects. At the present time, the methodology and usefulness of meta-analysis is under scrutiny. In the first part of this paper, we summarize the limitations of meta-analysis and make suggestions for improvements. In the second part, we illustrate strengths and limitations using examples of meta-analyses and subsequent large trials that address the same question. We develop the hypothesis that the size of the meta-analysis may be a useful measure of reliability. Small meta-analyses (i.e., those with less than 200 outcome events) may only be useful for summarizing the available information and generating hypotheses for future research. The results of small meta-analyses should be regarded with caution, even if the p value shows extreme statistical significance. Larger meta-analyses (i.e., those with several hundred events) are likely to be more reliable and may be clinically useful. Well-conducted meta-analyses of large trials using individual patient data may provide the best estimates of treatment effects in the cohort overall and in clinically important subgroups.

Long-Term Oral Anticoagulant Therapy in Patients With Unstable Angina or Suspected Non–Q-Wave Myocardial Infarction Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study Results

BACKGROUNDnPatients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized controlled studies.nnnMETHODS AND RESULTSnIn phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized ratio (INR) of 1.5+/-0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1. 66; 95% CI, 0.62 to 4.44; P=0.31). The rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48; 95% CI, 0.80 to 7.75; P=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 patients were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean INR of 2.3+/-0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV death, new MI, and refractory angina at 3 months were 5. 1% in the warfarin group and 12.1% in the standard group (RR, 0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and 13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR, 0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfarin group and 1 in the control group experienced a major bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36; P=0.004).nnnCONCLUSIONSnLong-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation.

Magnesium in acute myocardial infarction

Clinical investigators have long pursued the elusive dream of finding a cheap, safe treatment that reduces mortality and morbidity in a common condition. Many investigators had hoped that magnesium given intravenously to patients with acute myocardial infarction might be such a treatment. Were they justified?nnSmall trials reporting the use of magnesium in acute myocardial infarction have been reported intermittently for 20 years. The rationale for these studies came partly from observations of differences in heart attack rates associated with geographical variations in magnesium in the water supply and partly from laboratory studies showing that magnesium had cardioprotective effects during ischaemia and that myocardial magnesium concentrations were relatively low during acute ischaemia.1nnResearch on animals has shown that magnesium is a peripheral and coronary vasodilator, has antiarrhythmic effects, decreases reperfusion injury, and has antiplatelet effects in some species.1 The clinical importance of these findings is, however, still uncertain. Experimental studies often do not have the same rigorous design, conduct, and analysis that are now expected from clinical research. Few experimental studies are randomised or blinded. Furthermore, publication bias is likely, with positive results being more likely to be reported than negative ones—especially when the subject is a relatively new hypothesis.nnAn informal review of the results of the early clinical trials in acute myocardial infarction indicated a trend towards a lower mortality with intravenous magnesium, with this difference being statistically significant in only one trial.2 That trial also found a reduction in arrhythmias. These impressions were subsequently confirmed by a formal metaanalysis.3 The data came, however, from only 1300 patients with a …

Maximizing benefits of therapies in acute myocardial infarction

Major advances in the management of acute myocardial infarction have been achieved by a combination of careful experimental work and development of effective pharmacologic and interventional strategies in conjunction with the conduct of large, reliable randomized trials. Current trials indicate that a combination of thrombolytic therapy, aspirin, and intravenous followed by oral beta blockers reduces mortality. There are a number of additional promising interventions, such as intravenous magnesium, nitrates, and the newer antithrombin agents. However, before these agents are used widely in clinical practice, clear proof of benefit and adequate safety should be available from the ongoing randomized trials. Following discharge from the hospital, long-term therapy with aspirin and beta blockers should be considered in all patients. In patients with heart failure and low ejection fraction, angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality, reinfarction, and the need for further hospitalizations for heart failure. Therefore, these therapies, in conjunction with risk factor modification (cessation of cigarette smoking, treatment of hypercholesterolemia, treatment of hypertension), should be considered in all appropriate patients. A number of new strategies for the prevention of atherosclerosis and its complications are currently being evaluated in prospective randomized trials. These include the natural antioxidant vitamins, estrogen replacement therapy, tamoxifen therapy, and ACE inhibitors in patients without evidence of heart failure or left ventricular dysfunction.