Harold I. Palevsky

The Clinical Course of Pulmonary Embolism

BACKGROUND Pulmonary embolism is a potentially fatal disorder. Information about the outcome of clinically recognized pulmonary embolism is sparse, particularly given that new treatments for more seriously ill patients are now available. METHODS We prospectively followed 399 patients with pulmonary embolism diagnosed by lung scanning and pulmonary angiography, who were enrolled in a multicenter diagnostic trial. We reviewed all hospitalizations, all new investigations of pulmonary embolism, and all deaths among the patients within one year of diagnosis. RESULTS Of the 399 patients, 375 (94 percent) received treatment for pulmonary embolism, usually conventional anticoagulation. Only 10 patients (2.5 percent) died of pulmonary embolism; 9 of them had clinically suspected recurrent pulmonary embolism. Clinically apparent pulmonary embolism recurred in 33 patients (8.3 percent), of whom 45 percent died during follow-up. Ninety-five patients with pulmonary embolism (23.8 percent) died within one year. The conditions associated with these deaths were cancer (relative risk, 3.8; 95 percent confidence interval, 2.3 to 6.4), left-sided congestive heart failure (relative risk, 2.7; 95 percent confidence interval, 1.5 to 4.6), and chronic lung disease (relative risk, 2.2; 95 percent confidence interval, 1.2 to 4.0). The most frequent causes of death in patients with pulmonary embolism were cancer (in 34.7 percent), infection (22.1 percent), and cardiac disease (16.8 percent). CONCLUSIONS When properly diagnosed and treated, clinically apparent pulmonary embolism was an uncommon cause of death, and it recurred in only a small minority of patients. Most deaths were due to underlying diseases. Patients with pulmonary embolism who had cancer, congestive heart failure, or chronic lung disease had a higher risk of dying within one year than did other patients with pulmonary embolism.

Two-dimensional and Doppler-echocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension.

To determine correlates of survival in primary pulmonary hypertension, we compared 41 echocardiography-Doppler and nine catheterization parameters with outcome in 26 patients. Mean follow-up was 19.7 months in survivors; mean survival was 4.8 months in 16 nonsurvivors. Cox life-table univariate analysis correlated two echocardiographic, three Doppler, and three catheterization variables with poor survival (p less than or equal to 0.05), and chi 2 analysis ensured the best critical values: severity of pericardial effusion, heart rate of more than 87 beats/min, pulmonic flow acceleration time of less than 62 msec, tricuspid early flow deceleration (T-DEC) equal to or less than -300 cm2/sec, mitral early flow-to-atrial flow velocity ratio (M-E/A) equal to or less than 1.0, catheterization cardiac index (CI) equal to or less than 2.3 l/min/m2, mean pulmonary artery pressure of more than 61 mm Hg, and diastolic pulmonary artery pressure of more than 43 mm Hg. Multivariate life-table analysis of noninvasive variables revealed the severity of pericardial effusion to be independently significant (p = 0.006), whereas analysis of catheterization variables revealed cardiac index to be independently significant (p = 0.014). Combined multivariate analysis did not differ from the noninvasive results alone. Categorical modeling of the eight significant variables split at their critical values (present or absent) revealed M-E/A, T-DEC, and CI to be independently significant by multivariate analysis (p = 0.0014). Analysis of the five echocardiography-Doppler variables alone revealed M-E/A, T-DEC, and heart rate to be independently significant (p = 0.0016). In both cases, mortality increased with the number of critical values reached.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents.

The use of pharmacologic agents in the treatment of pulmonary hypertension has not proved to be uniformly successful or predictable. One possible reason for the vagaries in response is that the pulmonary vascular lesions are not consistent. We examined the relation between the structure of the pulmonary resistance vessels in unexplained (primary) pulmonary hypertension and the response to pulmonary vasodilators. Our study involved 19 patients with clinically unexplained pulmonary hypertension (mean pressure, 59 +/- 14 mm Hg). After characterizing them clinically and performing control hemodynamic measurements, we determined the acute effects of a series of vasodilator agents that have different mechanisms of action. In 16 patients, lung biopsy material was related to the hemodynamic studies; in nine patients, including six who had undergone open lung biopsy, the hemodynamic studies were related to the pathologic changes found at autopsy. Histologic specimens from all 19 patients were evaluated qualitatively and sorted into three subsets of hypertensive pulmonary arteriopathy: medial hypertrophy (with minimal intimal proliferation), arteriopathy with plexiform lesions (associated predominantly with concentric laminar intimal proliferation and fibrosis), and arteriopathy with microthrombotic lesions (associated predominantly with eccentric intimal proliferation and fibrosis). The 16 lung biopsies were also quantitated by morphometric techniques. Using a decrease in calculated pulmonary vascular resistance of more than 30% accompanied by a decrease in mean pulmonary arterial pressure of at least 10% to define vasodilation, only four patients were responders. The patients varied considerably in their responses to different vasodilator agents. Patients with similar clinical and hemodynamic profiles differed considerably with respect to the nature of their pulmonary vascular obstructive lesions and their responses to vasodilator agents. Qualitative histologic examination of lung tissue did not provide a basis for predicting how individual patients would respond to vasodilator agents. However, quantitative morphologic analysis of the initial open lung biopsy specimens did prove helpful in predicting acute responsiveness to vasodilator agents and the subsequent clinical course of these patients with unexplained (primary) pulmonary hypertension. An intimal area of more than 18% of the vascular cross-sectional area had an 85% predictive value for identifying the patients who did poorly during the first 36 months of follow-up.

Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials

Background— Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (&Dgr;6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in &Dgr;6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. Methods and Results— First, to determine whether &Dgr;6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the &Dgr;6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. &Dgr;6MWD accounted for 22.1% (95% confidence interval, 12.1%– 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in &Dgr;6MWD of 22.4 m (95% confidence interval, 17.4–27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33–0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Conclusions— Our results suggest that &Dgr;6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.

Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report

OBJECTIVE Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence. METHODS This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus. RESULTS Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded. CONCLUSIONS Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

Pulmonary artery hemodynamics in primary pulmonary hypertension

OBJECTIVES The present investigation compared and contrasted steady and pulsatile pulmonary hemodynamics at rest and during exercise in patients with primary pulmonary hypertension and normal control subjects. BACKGROUND A complete description of the relation between pressure and flow in the pulmonary circulation includes both steady and pulsatile hemodynamic behavior. Patients with primary pulmonary hypertension provide a unique opportunity to study the effects of primary alterations in pulmonary vasculature on pulmonary artery vascular hydraulic load. METHODS Catheter tip pressure and velocity recordings from the main pulmonary artery in 8 patients with primary pulmonary hypertension and 10 control subjects were used to derive the pulmonary artery input impedance spectrum and the extent of pulse wave reflection at rest and during exercise. RESULTS As expected, in patients with primary pulmonary hypertension, mean pulmonary artery pressure (50 +/- 10 mm Hg) and pulmonary vascular resistance (880 +/- 446 dynes.s.cm-5) were markedly elevated at rest and remained so during exercise (mean pressure 71 +/- 15 mm Hg, mean resistance 750 +/- 530 dynes.s.cm-5). Pulmonary artery characteristic impedance was elevated at rest and did not change with exercise (rest 55 +/- 25 dynes.s.cm-5; exercise 66 +/- 33 dynes.s.cm-5). Measures of arterial wave reflection indicated that the extent of wave reflection in the pulmonary bed in those with primary pulmonary hypertension is large at rest (reflection coefficient 0.89 +/- 0.09) and that the composite reflected wave arrived during the midportion of right ventricular ejection. Although the extent of wave reflection decreased with exercise (reflection coefficient 0.81 +/- 0.10, p < 0.05), the magnitude and timing of these reflections remained adverse. Furthermore, in patients with primary pulmonary hypertension, the stroke volume response to exercise was strongly related to rest levels of pulmonary artery diastolic pressure, pulmonary vascular resistance and the reflection factor, whereas no such relation was found in the control subjects. CONCLUSIONS In addition to the expected abnormalities in steady measures of pulmonary artery hemodynamics at rest in patients with primary pulmonary hypertension, rest and exercise measures of oscillatory behavior (characteristic impedance and pulse wave reflection) are perturbed. Measures of steady and pulsatile behavior, particularly wave reflection, appear to have an important role in the exercise response of these patients.

DIAGNOSING PULMONARY EMBOLISM : NEW FACTS AND STRATEGIES

PURPOSE To provide a clinical approach to the diagnosis of pulmonary embolism. DATA IDENTIFICATION An English-language literature search using MEDLINE (1982 to 1990) and bibliographic reviews of textbooks and review articles. STUDY SELECTION In addition to several reviews, studies that evaluated the diagnostic technology of pulmonary embolism were selected. Preference was given to studies with a prospective design, particularly those done within the past decade. DATA EXTRACTION Studies were assessed independently by three unblinded observers. Data were chosen to describe the efficacy of diagnostic technology on the basis of disease prevalence, sensitivity and specificity, and predictive value. RESULTS OF DATA ANALYSIS A normal lung scan or pulmonary angiogram rules out the diagnosis of clinically important pulmonary embolism with at least 95% certainty. Lung scan interpretations indicating high or low probability have approximately a 15% error in diagnosing or ruling out pulmonary embolism. The accuracy of either scan result improves when the clinical suspicion of pulmonary embolism matches the lung scan result. Serial impedance plethysmography of the lower extremities may exclude thromboembolism with 95% certainty in patients without high-probability lung scan results or cardiopulmonary disease. CONCLUSIONS The combination of clinical suspicion and the results of the lung scan and impedance plethysmography appear to offer acceptable diagnostic accuracy in evaluating many patients suspected of having pulmonary embolism. The usefulness of this approach for patients with cardiopulmonary disease is still unknown.

Aspirin and warfarin for thromboembolic disease after total joint arthroplasty

This study compares the benefits of aspirin and warfarin prophylactic agents for patients with thromboembolic disease after total joint arthroplasty. It is a prospective randomized study of 388 patients having total hip or total knee surgery. All consecutive patients having total hip or total knee surgery were entered into this study and evaluated with preoperative and postoperative ventilation perfusion scans and a postoperative venogram. The aspirin and warfarin treatment groups were compared by size and location of venographically revealed clots and changes in ventilation perfusion scans. The results showed that there was no difference in the size or location of deep venous thrombosis in the aspirin or warfarin treatment groups. The venogram was negative in 44.5% of patients; 28.8% had small calf clots, 16% had large calf clots, 3.9% had popliteal clots, and 6.7% had femoral clots. Patients with total knee replacement had a 2.6 times greater incidence of calf deep venous thrombosis than patients with total hip replacement. There was no difference between the aspirin and warfarin groups in the incidence of changes in ventilation perfusion scans (18.9%). There was no difference between the 2 groups in bleeding complications. The results suggest that aspirin and warfarin are equivalent in prophylaxis against thromboembolic disease, as determined by prevention of venographic changes or changes in ventilation perfusion scans.

Bilateral versus single lung transplantation for chronic obstructive pulmonary disease

OBJECTIVE Traditionally, despite ventilation/perfusion mismatch, single lung transplantation has been the mainstay for end-stage chronic obstructive pulmonary disease. We tested the hypothesis that bilateral sequential lung transplantation has better short- and intermediate-term results than single lung transplantation for chronic obstructive pulmonary disease. METHODS One hundred twenty-six consecutive lung transplants have been performed from November 1991 to March 1996. Seventy-six have been for chronic obstructive pulmonary disease. The diagnosis of this disease includes emphysema (80.3%), alpha 1-antitrypsin deficiency (9.2%), lymphangioleiomyomatosis (7.9%), and obliterative bronchiolitis (2.6%). Twenty-nine transplants have been bilateral and 47 have been single. Mean age was 55.3 for patients having single lung transplantation and 48.8 for those having bilateral lung transplantation (p = 0.001). The distribution of the diagnoses was similar between the two groups. At 6 months, there were 29 survivors of single lung transplantation and 20 survivors of bilateral lung transplantation, with complete data for evaluation. Pulmonary function tests and 6-minute walk tests were evaluated at a mean of 15.4 and 12.8 months after transplantation, respectively. RESULTS Sixty-day mortality was 21.3% for single lung transplantation versus only 3.45% for bilateral lung transplantation (p = 0.03). Additionally, Kaplan-Meier analysis revealed 1- and 2-year survivals of 71.1% and 63.3% for single lung transplantation versus 90% and 90% for bilateral lung transplantation, respectively. Multiple major morbidities were analyzed. Primary graft failure was significantly reduced in the bilateral group (p = 0.049). Both 6-minute walk tests and forced expiratory volume in 1 second were improved from baseline by both single and bilateral lung transplantation (p = 0.001). CONCLUSIONS Bilateral lung transplantation improves forced expiratory volume in 1 second and 6-minute walk tests significantly over single lung transplantation (p < 0.0001). Both perioperative mortality and Kaplan-Meier survival (to 3 years) are significantly improved when bilateral rather than single lung transplantation is used for chronic obstructive pulmonary disease in our series (p < 0.05). This is probably the result of significantly reduced primary graft failure.

Randomized Clinical Trial of Aspirin and Simvastatin for Pulmonary Arterial Hypertension ASA-STAT

Background— Pulmonary arterial hypertension (PAH) is a progressive disease that causes exercise limitation, heart failure, and death. We aimed to determine the safety and efficacy of aspirin and simvastatin in PAH. Methods and Results— We performed a randomized, double-blind, placebo-controlled 2×2 factorial clinical trial of aspirin and simvastatin in patients with PAH receiving background therapy at 4 centers. A total of 92 patients with PAH were to be randomized to aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo. The primary outcome was 6-minute walk distance at 6 months. Sixty-five subjects had been randomized when the trial was terminated by the Data Safety and Monitoring Board after an interim analysis showed futility in reaching the primary end point for simvastatin. After adjustment for baseline 6-minute walk distance, there was no significant difference in the 6-minute walk distance at 6 months between aspirin (n=32) and placebo (n=33; placebo-corrected difference −0.5 m, 95% confidence interval −28.4 to 27.4 m; P=0.97) or between simvastatin (n=32) and placebo (n=33; placebo-corrected difference −27.6 m, 95% confidence interval −59.6 to 4.3 m; P=0.09). There tended to be more major bleeding episodes with aspirin than with placebo (4 events versus 1 event, respectively; P=0.17). Conclusions— Neither aspirin nor simvastatin had a significant effect on the 6-minute walk distance, although patients randomized to simvastatin tended to have a lower 6-minute walk distance at 6 months. These results do not support the routine treatment of patients with PAH with these medications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00384865.