By Michael H. Crawford, MD

Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: A cluster randomized trial of the pulmonary embolism rule-out criteria (PERC) compared to usual care for patients estimated to be at low risk of pulmonary embolus (PE) in EDs showed that PERC was non-inferior to usual care at identifying patients who would be free of symptomatic PE at three months, resulting in less use of healthcare resources.

SOURCES: Freund Y, Cachanado M, Aubry A, et al. Effect of the pulmonary embolism rule-out criteria on subsequent thromboembolic events among low-risk emergency department patients: The PROPER randomized clinical trial. JAMA 2018;319:559-566.

Kline JA. Utility of a clinical prediction rule to exclude pulmonary embolism among low-risk emergency department patients: Reason to PERC up. JAMA 2018;319:551-553.

The pulmonary embolism rule-out criteria (PERC) for use in EDs consists of eight clinical criteria that are used to identify a population at low risk of PE in whom further testing would be associated with an unfavorable risk-benefit ratio. Observational studies have demonstrated its usefulness, but the lack of prospective, randomized trials has hampered its adoption. Thus, investigators from 14 EDs in France conducted a multicenter, non-inferiority, randomized, clinical trial to test the hypothesis that a PERC score of 0 would identify patients in whom the diagnosis of PE can be excluded safely. Patients who presented with new-onset or worsening dyspnea or chest pain and a low clinical gestalt of PE (likelihood < 15%) were included. Patients were excluded if another diagnosis was obvious, if they were in severe distress (e.g., hypotensive), receiving anticoagulants, or had contra-indications to contrast CT of the pulmonary arteries (CTPA).

The PERC criteria were: O2 saturation < 94%, pulse > 100 bpm, age > 50 years, unilateral leg swelling, hemoptysis, recent trauma or surgery, prior PE or deep venous thrombosis, and estrogen use. Seven EDs used PERC, and seven did not. At six months, there was a two-month break. Then, the EDs switched to the opposite strategy. In the PERC groups, if the score was 0, no further testing was conducted. If the PERC was ≥ 1 (maximum of 8), the usual strategy was followed: measuring D-dimer and then CTPA if the D-dimer was positive. In the control group, the usual strategy was applied to all. If CTPA was inconclusive, pulmonary ventilation perfusion (VQ) scanning or lower leg ultrasound was performed. All patients were followed for three months. The primary outcome of the study was the occurrence of a symptomatic thromboembolic event.

After excluding protocol violations, 1,749 patients were included in the per-protocol population (902 controls and 847 PERC). The mean age was 44 years, and 51% were women. In the PERC groups, there were 459 PERC-negative patients. PE was diagnosed in 2.7% of the control patients and 1.5% of the PERC group. The proportion of patients undergoing CTPA was less in the PERC group (13% vs. 23%; P < 0.001). ED length of stay also was lower in the PERC group (mean reduction, 36 minutes).

Only one PE was missed by the PERC rule initially, but because of ongoing pain and a positive D-dimer, a CTPA was conducted, which was negative, but a VQ scan showed small defects. There was no difference in mortality at three months. The non-inferiority of PERC was confirmed. The authors concluded that in low-risk ED patients undergoing evaluation for possible PE, randomization to a PERC strategy vs. usual care did not result in an inferior rate of thromboembolic events over three months, confirming that this is a safe strategy in such patients.

COMMENTARY

Many believe that with the development of D-dimer and CTPA at the turn of this century, ED patients are over-tested for PE in the United States. Given that CTPA can result in renal injury (14%), a false-positive diagnosis of PE (5%), and possibly later breast cancer in women, various clinical scores were developed to help identify low-risk patients who probably didn’t need further testing. The PERC rule has the advantage of first using the clinicians’ gestalt that the patient has a < 15% chance of developing a PE. Then, if all eight PERC criteria are negative, the person is at such a low risk of PE that more harm than good is likely to result from further testing.

Observational studies in the United States and elsewhere have confirmed the utility of the rule, but two retrospective studies in Europe did not. Hence, these investigators from France designed and carried out this real-world randomized, clinical trial of the use of PERC vs. usual care. Both strategies employed D-dimer and CTPA if deemed necessary. The endpoint was symptomatic PE in the three months after the ED visit. In the PERC group, only one clinically apparent PE was missed, albeit a small one only detected by VQ scanning. Thus, the criteria for non-inferiority were met. Since the PERC strategy identified PE in 1.5% of the PERC group and 2.17 of the usual care (control) group, the PERC rule probably missed some small sub-segmental PEs. Whether such small PEs require treatment or not is unresolved. Clearly, no clinically significant PEs were missed by the PERC strategy. Studies have shown that usual care detects PE in 5% of patients, so the rate of 2.7% in the control group is low, which speaks to the value of clinical gestalt for initial screening. If the risk is low, then PERC can be applied. In the United States, most EDs would also perform a D-dimer in almost all patients, but if PERC and D-dimer are negative, CTPA or other imaging tests could be avoided. This strategy was not tested in the French study.

There were limitations to this study. It was not a randomized trial at the patient level, which would have been challenging to conduct, but rather a cluster randomization of EDs. Also, 54 patients were lost to follow-up, which could have influenced the results. No cost data were presented, although there was clearly less testing, shorter ED stays, and fewer hospital admissions in the PERC group. However, a negative PERC could have led to more testing for other conditions. Despite these shortcomings, this trial adds considerable weight to the use of the PERC rule in low-risk patients undergoing evaluation for possible PE.