David L. Sackett

Benefit of Carotid Endarterectomy in Patients with Symptomatic Moderate or Severe Stenosis

BACKGROUND Previous studies have shown that carotid endarterectomy in patients with symptomatic severe carotid stenosis (defined as stenosis of 70 to 99 percent of the luminal diameter) is beneficial up to two years after the procedure. In this clinical trial, we assessed the benefit of carotid endarterectomy in patients with symptomatic moderate stenosis, defined as stenosis of less than 70 percent. We also studied the durability of the benefit of endarterectomy in patients with severe stenosis over eight years of follow-up. METHODS Patients who had moderate carotid stenosis and transient ischemic attacks or nondisabling strokes on the same side as the stenosis (ipsilateral) within 180 days before study entry were stratified according to the degree of stenosis (50 to 69 percent or <50 percent) and randomly assigned either to undergo carotid endarterectomy (1108 patients) or to receive medical care alone (1118 patients). The average follow-up was five years, and complete data on outcome events were available for 99.7 percent of the patients. The primary outcome event was any fatal or nonfatal stroke ipsilateral to the stenosis for which the patient underwent randomization. RESULTS Among patients with stenosis of 50 to 69 percent, the five-year rate of any ipsilateral stroke (failure rate) was 15.7 percent among patients treated surgically and 22.2 percent among those treated medically (P=0.045); to prevent one ipsilateral stroke during the five-year period, 15 patients would have to be treated with carotid endarterectomy. Among patients with less than 50 percent stenosis, the failure rate was not significantly lower in the group treated with endarterectomy (14.9 percent) than in the medically treated group (18.7 percent, P=0.16). Among the patients with severe stenosis who underwent endarterectomy, the 30-day rate of death or disabling ipsilateral stroke persisting at 90 days was 2.1 percent; this rate increased to only 6.7 percent at 8 years. Benefit was greatest among men, patients with recent stroke as the qualifying event, and patients with hemispheric symptoms. CONCLUSIONS Endarterectomy in patients with symptomatic moderate carotid stenosis of 50 to 69 percent yielded only a moderate reduction in the risk of stroke. Decisions about treatment for patients in this category must take into account recognized risk factors, and exceptional surgical skill is obligatory if carotid endarterectomy is to be performed. Patients with stenosis of less than 50 percent did not benefit from surgery. Patients with severe stenosis (> or =70 percent) had a durable benefit from endarterectomy at eight years of follow-up.

Bias in analytic research.

Publisher Summary This chapter focuses on the bias in analytic research. Case-control studies are attractive. They can be executed quickly and at low cost, even when the disorders of interest are rare. The execution of pilot case-control studies is becoming automated; strategies have been devised for the “computer scanning” of large files of hospital admission diagnoses and prior drug exposures, with detailed analyses carried out in the same data set on an ad hoc basis. As evidence of their growing popularity, when one original article was randomly selected from each issue of The New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association for the years 1956, 1966, and 1976, the proportion that reported case-control analytic studies increased fourfold over these two decades; however, the proportion reporting cohort analytic studies fell by half; a general trend toward fewer study subjects but more study authors was also noted.

An assessment of clinically useful measures of the consequences of treatment.

WITH neither the time nor the resources available to prevent, detect, or treat every disorder in every patient, which preventive, diagnostic, or therapeutic interventions should take priority? When...

Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial.

We performed a randomized, double-blind, placebo-controlled trial in 555 patients with unstable angina who were hospitalized in coronary care units. Patients received one of four possible treatment regimens: aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily), both, or neither. They were entered into the trial within eight days of hospitalization and were treated and followed for up to two years (mean, 18 months). The incidence of cardiac death and nonfatal myocardial infarction, considered together, was 8.6 per cent in the groups given aspirin and 17.0 per cent in the other groups, representing a risk reduction with aspirin of 51 per cent (P = 0.008). The corresponding figures for either cardiac death alone or death from any cause were 3.0 per cent in the groups given aspirin and 11.7 per cent in the other groups, representing a risk reduction of 71 per cent (P = 0.004). Analysis by intention to treat yielded smaller risk reductions with aspirin of 30 per cent (P = 0.072), 56 per cent (P = 0.009), and 43 per cent (P = 0.035) for the outcomes of cardiac death or nonfatal acute myocardial infarction, cardiac death alone, and all deaths, respectively. There was no observed benefit of sulfinpyrazone for any outcome event, and there was no evidence of an interaction between sulfinpyrazone and aspirin. Considered together with the results of a previous clinical trial, these findings provide strong evidence for a beneficial effect of aspirin in patients with unstable angina.

Diagnosis and Treatment of Chronic Arterial Insufficiency of the Lower Extremities: A Critical Review

Atherosclerosis is the most common cause of chronic arterial occlusive disease of the lower extremities. The arterial narrowing or obstruction that occurs as a result of the atherosclerotic process reduces blood flow to the lower limb during exercise or at rest. A spectrum of symptoms results, the severity of which depends on the extent of the involvement and the available collateral circulation. Thus, symptoms may range from intermittent claudication to pain at rest. Intermittent claudication denotes pain that develops in the affected limb with exercise and is relieved with rest. This pain usually occurs distal to the arterial narrowing or obstruction. Since the superficial femoral and popliteal arteries are the vessels most commonly affected by the atherosclerotic process, the pain of intermittent claudication is most often localized to the calf. The distal aorta and its bifurcation into the two iliac arteries are the next most frequent sites of involvement. Narrowing of these arteries may produce pain in the buttocks or the thighs as well as the legs. Epidemiological studies indicate that up to 5% of men and 2.5% of women 60 years of age or older have symptoms of intermittent claudication.1 2 The prevalence is at least threefold higher when sensitive noninvasive tests are used to make the diagnosis of arterial insufficiency in asymptomatic and symptomatic individuals.3 The symptoms of chronic arterial insufficiency of the lower extremities progress rather slowly over time. Thus, after 5 to 10 years, more than 70% of patients report either no change or improvement in their symptoms, while 20% to 30% have progressive symptoms and require intervention, and less than 10% need amputation.4 5 Despite the relatively benign prognosis for the affected limb, however, symptoms of intermittent claudication should be viewed as a sign of systemic atherosclerosis. This explains why, compared with …

Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

The utility of different health states as perceived by the general public.

A series of ‘scenarios’ describing the physical, social and emotional characteristics, limitations and duration of different health states have been successfully applied to a random sample of the general public in order to determine their social utility. The resulting mean daily health state utilities differ among disorders and vary with age, the duration of the disorder, the ‘label’ used to describe the disorder and the health status of the respondent. These health state utilities have considerable potential application in the planning and financing of health services.

The Architecture of Diagnostic Research

This is the second in a series of five articles Considerable effort has been expended at the interface between clinical medicine and scientific methods to achieve the maximum validity and usefulness of diagnostic tests. This article focuses on the specific kinds of questions that arise in diagnostic research and the study architectures (the conversions of these clinical questions into appropriate research designs) used to answer them. As an example we shall take shall take assessment of the value of the plasma concentration of B-type natriuretic peptide (BNP) in the diagnosis of left ventricular dysfunction.1 Randomised controlled trials are dealt with elsewhere. As in other forms of clinical research, there are several different ways studying the potential or real diagnostic value of a physical sign or laboratory test, and each is appropriate to one kind of question and inappropriate for others. Among the possible questions about the relation between a putative diagnostic test and a target disorder (for example, the concentration of BNP and left ventricular dysfunction), four are most relevant. #### Summary points Diagnostic studies should match methods to diagnostic questions The keys to validity in diagnostic test studies are Both specificity and sensitivity may change as the same diagnostic test is applied in primary, …

Warfarin Sodium versus Low-Dose Heparin in the Long-Term Treatment of Venous Thrombosis

Acute deep-vein thrombosis is usually treated with intravenous heparin for a number of days, then with oral anticoagulants for weeks to months. We have compared adjusted-dose warfarin sodium with fixed low-dose subcutaneous heparin in the prevention of recurrent deep-vein thrombosis. Sixty-eight patients with acute deep-vein thrombosis confirmed by venography were treated with intravenous heparin and then randomized to secondary prophylaxis. Nine of 35 patients receiving subcutaneous heparin, but none of 33 receiving warfarin sodium, had new episodes of objectively documented venous thromboembolism (P = 0.001). Seven patients on warfarin sodium experienced bleeding complications (of which four were major), as compared with no patients receiving subcutaneous heparin (P less than 0.005). Thus, adjusted-dose warfarin sodium is more effective than low-dose subcutaneous heparin in preventing recurrent venous thromboembolism, but its use is accompanied by a significant risk of bleeding.

Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial *

BACKGROUND Endarterectomy benefits certain patients with carotid stenosis, but benefits are lessened by perioperative surgical risk. Acetylsalicylic acid lowers the risk of stroke in patients who have experienced transient ischaemic attack and stroke. We investigated appropriate doses and the role of acetylsalicylic acid in patients undergoing carotid endarterectomy. METHODS In a randomised, double-blind, controlled trial, 2849 patients scheduled for endarterectomy were randomly assigned 81 mg (n=709), 325 mg (n=708), 650 mg (n=715), or 1300 mg (n=717) acetylsalicylic acid daily, started before surgery and continued for 3 months. We recorded occurrences of stroke, myocardial infarction, and death. We compared patients on the two higher doses of acetylsalicylic acid with patients on the two lower doses. FINDINGS Surgery was cancelled in 45 patients, none were lost to follow-up by 30 days, and two were lost by 3 months. The combined rate of stroke, myocardial infarction, and death was lower in the low-dose groups than in the high-dose groups at 30 days (5.4 vs 7.0%, p=0.07) and at 3 months (6.2 vs 8.4%, p=0.03). In an efficacy analysis, which excluded patients taking 650 mg or more acetylsalicylic acid before randomisation, and patients randomised within 1 day of surgery, combined rates were 3.7% and 8.2%, respectively, at 30 days (p=0.002) and 4.2% and 10.0% at 3 months (p=0.0002). INTERPRETATION The risk of stroke, myocardial infarction, and death within 30 days and 3 months of endarterectomy is lower for patients taking 81 mg or 325 mg acetylsalicylic acid daily than for those taking 650 mg or 1300 mg.