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Clinicians routinely apply randomized trial evidence to their patients who meet study selection criteria. However, little is known about how clinicians interpret conflicting subgroup data.We mailed a self-administered survey to all practicing cardiologists (n = 309) and 695 randomly chosen other specialists in Ontario, Canada. The survey presented 6 hypothetical trials where a subgroup result deviated from the overall result. We also elicited responses to some general statements about clinical evidence and subgroups.Completed surveys were received from 435 physicians (44%). Faced with overall benefit but no apparent treatment effect in a subgroup, almost 44% would exclude subgroup-type patients, notwithstanding the hazard of beta error. Given overall harm but significant benefit for a subgroup, responses were split approximately 60:40 between continuing conventional therapy for all and treating subgroup-type patients with the new drug. For an overall null result with a positive treatment-subgroup interaction term, 25% of respondents would continue conventional therapy, whereas 69% would adopt the new drug for subgroup-type patients. Physicians with an academic appointment, devoting more time to research, or with formal training in research methodology were more likely to ignore subgroups unless a treatment-subgroup interaction term was significant (P values ranging from .018 to.0001). Asked if in general they paid special attention to individual subgroup results, respondents were again divided with 37.5% agreeing, 39.5% disagreeing, and the rest undecided.Clinicians disagree sharply in interpretation of clinical trials when the overall and subgroup results diverge. Clearer guidelines are needed for undertaking, reporting, and interpreting subgroup analyses.

Background The overall effect sizes estimated from randomized clinical trials may not apply similarly to all patients. Univariate subgroup analyses are often used to help determine the generalizability of a trial's results, but may themselves be misleading. We reanalyzed the Studies of Left Ventricular Dysfunction (SOLVD) to determine whether the treatment effect depended on the patients' baseline prognosis, defined on the basis of multiple clinical variables. Methods The SOLVD prevention (4228 patients) and the SOLVD treatment (2569 patients) trials were randomized, double-blind trials that studied the effect of enalapril in patients with reduced left-ventricular function or congestive heart failure. We combined both SOLVD populations and compared the results of a univariate analysis to a multivariate approach in which 3 patient subgroups were defined according to baseline risks for the combined end point of death or hospitalization for heart failure. Results Enalapril treatment resulted in 24% fewer events. The strongest predictors of an event were ejection fraction, New York Heart Association classification and age, antiplatelet agents, history of diabetes mellitus, treatment with digoxin or diuretics, and race. Only ejection fraction produced a significant treatment interaction ( P =.004). Consistent with the original SOLVD reports, this interaction was also demonstrable when ejection fraction was scaled into tertiles and examined on its own ( P =.012). However, there was no interaction present when patients were divided into tertiles of multifactorial baseline risk. Conclusions We confirmed the treatment effect of enalapril, the impact of left-ventricular systolic function, and the negative prognostic importance of diabetes mellitus in this population. Although ejection fraction led to a subgroup-treatment interaction in the main SOLVD publications, a multifactorial approach to prognostic grouping abolished the interaction. These findings highlight the limitations of univariate subgroup analyses and illustrate that multivariate risk group analysis may be a complementary method for assessing the generalizability of the overall treatment effects observed in randomized trials. (Am Heart J 2002;144:941-7.)

Background The objective of this study was to determine how subgroup analyses are performed in large randomized trials of cardiovascular pharmacotherapy. Methods and Results We reviewed 67 randomized, double-blind, controlled trials involving pharmacotherapy in at least 1000 patients with unstable angina, myocardial infarction, left ventricular dysfunction, or heart failure with clinical outcomes as primary end points, published between 1980 and 1997. Nine had no subgroup analyses but 43 reported on 5 or more subgroups and 31 reported subgroups without formal statistical tests for treatment-subgroup interactions. In most trials, a rationale for subgroup selection was missing. All but 6 focused on single-factor subgroups. Conclusions Trial subgroups should ideally be defined a priori on 2 bases: single-factor subgroups with a strong rationale for biological response modification and multifactorial prognostic subgroups defined from baseline risks. However, single-factor subgroup analyses are often reported without a supporting rationale or formal statistical tests for interactions. We suggest that clinicians should interpret published subgroup-specific variations in treatment effects skeptically unless there is a prespecified rationale and a significant treatment-subgroup interaction. (Am Heart J 2000;139:952-61.)

Background: The aim of this study was to examine the acute hemodynamic and neurohormonal effects of the angiotensin II antagonist telmisartan relative to placebo in patients with chronic symptomatic (New York Heart Association class II to III) congestive heart failure and to explore the dose-response relation for these effects. Methods and Results: After baseline hemodynamic and neurohormonal measurements made with the use of a pulmonary artery and radial arterial catheter, 82 patients were randomly assigned to placebo or 10, 20, 40, or 80 mg of telmisartan in a double-blind fashion. Hemodynamic and neurohormonal measurements were carried out over 24 hours. Telmisartan caused significant decreases in systemic arterial, pulmonary arterial, and pulmonary capillary wedge pressures with evidence of a dose-response relation for each of these parameters. The drug had no significant effects on heart rate, cardiac index, or systemic vascular resistance. Telmisartan did not have consistent effects on either plasma norepinephrine or plasma atrial natriuretic peptide levels, although it did cause significant increases in both plasma renin activity and angiotensin II levels at higher doses. Conclusions: The acute administration of the angiotensin II antagonist telmisartan was associated with significant dose-dependent reductions in systemic arterial blood pressure and pulmonary pressures. Long-term follow-up studies are required to translate changes in hemodynamic parameters into a clinical benefit. (Am Heart J 1999;138:843-8.)

To determine the significance of the direction of ST segment deviation on admission of patients who evolved non-Q wave myocardial infarction (MI), 97 patients with initial ST segment depression were compared to 207 patients with initial ST segment elevation. Patients with ST segment depression developed smaller infarcts than those with ST segment elevation (creatine kinase MB isoenzyme 8.2 vs 13.3 gmEq/m2, p less than 0.002), but had a lower left ventricular ejection fraction on admission (44% vs 51%, p less than 0.001), more in-hospital complications, and a higher cumulative 1-year mortality (29% vs 11%, p less than 0.001) that could be accounted for by an excess of adverse baseline characteristics. Although a severity index (combining magnitude and extent of the initial ST segment deviation) was not useful for discriminating prognosis of patients with non-Q wave MI who presented with ST segment depression, it was useful in identifying a subgroup of patients with ST segment elevation with an adverse prognosis. The poor outcome of patients with non-Q wave MI presenting with either ST segment depression or severe ST segment elevation on admission suggests that patients in these subgroups should receive close surveillance and should possibly be considered for aggressive therapy.

Twenty-three patients underwent left ventricular aneurysmectomy without coronary artery bypass or other surgical procedure. Fourteen patients (Group 1) benefitted from surgery, and nine fared poorly (Group 2), including the four postoperative deaths. Among the 19 survivors, 17 had postoperative catheterizations. Pre- and postoperative left ventriculograms in the right anterior oblique projection were analyzed by planimetry of the aneurysmal and non-aneurysmal areas. This method provided data favorably altered by surgery in the improved patients and unchanged in the others. None of the preoperative ventriculographic measurements effectively separated the postoperative patient groups. The poor results in the Group 2 patients were of heterogeneous origin arising from pre-, peri- and postoperative factors. The more important factors were the largest and smallest aneurysms, surgically induced mitral insufficiency, and progressive coronary artery disease. Thus, the improvement in surgical results from better angiographic preoperative case selection is possible, but limited.

Summary Of 197 consecutive patients having aortocoronary bypass grafts over a 30 month period, 38 (19 per cent) had ECG evidence of myocardial infarction. The infarctions occurred more commonly in patients receiving multiple grafts. The infarctions were usually in areas supplied by grafted vessels. The infarctions occurred most often in the inferior wall, even when multiple vessels were grafted. Eleven patients with intraoperative infarction have had repeat postoperative coronary arteriograms. Seven had all grafts patent; three of these patients had hypokinesis of the infarcted wall. Four of the 11 patients had one or more occluded grafts; three of these patients had an area of hypokinesis. We conclude that intraoperative myocardial infarction is a common problem in aortocoronary bypass surgery and is not necessarily caused by graft occlusion.

Left ventricular rupture was studied in 849 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size. Although documented rupture occurred in only 14 cases (1.7%), it accounted for 14% of in-hospital mortality. Seven of the 14 ruptures occurred within 2 days and 10 within 4 days of the MB-creatine kinase-determined onset of infarction. Three easily determined baseline characteristics defined a set of patients with a markedly increased risk of myocardial rupture. Rupture was 9.2 times more likely to occur in patients with all of the following characteristics than in the remaining patients: (1) no history of previous angina or myocardial infarction, (2) ST segment elevation or signs of Q wave development on the initial ECG, and (3) peak MB-creatine kinase value (greater than or equal to 150 IU/L). The risk of myocardial rupture with these three characteristics was 5.5%. Although these predictors are likely to be of little therapeutic value for free wall rupture, since most patients with that complication die within minutes of its onset, they may aid in alerting physicians to the early diagnosis and timely surgical correction of ventricular septal rupture.