Feasibility of Cardiac Rehabilitation Models in Kenya.

BACKGROUND: Heart failure (HF), is a leading cause of cardiovascular morbidity and mortality in Sub-Saharan Africa. Cardiac rehabilitation (CR) is known to improve functional capacity and reduce morbidity associated with HF. Although CR is a low-cost intervention, global access and adherence rates to CR remain poor. In regions such as Western Kenya, CR programs do not exist. We sought to establish the feasibility CR for HF in this region by testing adherence to institution and home-based models of CR. METHODS: One hundred participants with New York Heart Association (NYHA) class II and III HF symptoms were prospectively enrolled from a tertiary health facility in Western Kenya. Participants were non-randomly assigned to participate in one of two CR models based on their preference. Institution based cardiac rehabilitation (IBCR) comprised 36 facility-based exercise sessions over a period of 12 weeks. Home based cardiac rehabilitation (HBCR) comprised weekly pedometer guided exercise targets over a period of 12 weeks. An observational arm (OA) receiving usual care was also enrolled. The primary endpoint of CR feasibility was assessed based on study participants to adherence to at least 25% of exercise sessions. Secondary outcomes of change in NYHA symptom class, and six-minute walk time distance (6MWTD) were also evaluated. Data were summarized and analyzed as means (SD) and frequencies. Paired t-tests, Chi Square, Fisher's, and ANOVA tests were used for comparisons. FINDINGS: Mean protocol adherence was greater than 25% in both CR models; 46% ± 18 and 29% ± 11 (P < 0.05) among IBCR and HBCR participants respectively. Improvements by at least one NYHA class were observed among 71%, 41%, and 54%, of IBCR, HBCR and OA participants respectively. 6MWTD increased significantly by a mean of 31 ± 65 m, 40 ± 55 m and 38 ± 71 m in the IBCR, HBCR and OA respectively (P < 0.05). CONCLUSIONS: IBCR and HBCR, are feasible rehabilitation models for HF in Western Kenya. Whereas improvement in functional capacity was observed, effectiveness of CR in this population remains unknown. Future randomized studies evaluating effect size, long term efficacy, and safety of cardiac rehabilitation in low resource settings such as Kenya are recommended.

Community Health Workers Improve Linkage to Hypertension Care in Western Kenya.

BACKGROUND: Elevated blood pressure (BP) is the leading global risk factor for mortality. Delay in seeking hypertension care is associated with increased mortality. OBJECTIVES: This study investigated whether community health workers, equipped with behavioral communication strategies and smartphone technology, can increase linkage of individuals with elevated BP to a hypertension care program in western Kenya and significantly reduce BP. METHODS: The study was a cluster randomized trial with 3 arms: 1) usual care (standard training); 2) "paper-based" (tailored behavioral communication, using paper-based tools); and 3) "smartphone" (tailored behavioral communication, using smartphone technology). The co-primary outcomes were: 1) linkage to care; and 2) change in systolic BP (SBP). A covariate-adjusted mixed-effects model was used, adjusting for differential time to follow-up. Bootstrap and multiple imputation were used to handle missing data. RESULTS: A total of 1,460 individuals (58% women) were enrolled (491 usual care, 500 paper-based, 469 smartphone). Average baseline SBP was 159.4 mm Hg. Follow-up measures of linkage were available for 1,128 (77%) and BP for 1,106 (76%). Linkage to care was 49% overall, with significantly greater linkage in the usual care and smartphone arms of the trial. Average overall follow-up SBP was 149.9 mm Hg. Participants in the smartphone arm experienced a modestly greater reduction in SBP versus usual care (-13.1 mm Hg vs. -9.7 mm Hg), but this difference was not statistically significant. Mediation analysis revealed that linkage to care contributed to SBP change. CONCLUSIONS: A strategy combining tailored behavioral communication and mobile health (mHealth) for community health workers led to improved linkage to care, but not statistically significant improvement in SBP reduction. Further innovations to improve hypertension control are needed. (Optimizing Linkage and Retention to Hypertension Care in Rural Kenya [LARK]; NCT01844596).

Tailored Plans: The Next Step in a Long Evolution.

Medicaid transformation in North Carolina marks the next step in a lengthy history of caring for individuals with behavioral health challenges. "Tailored" health plans will cover people with severe mental illness, substance use disorders, intellectual/developmental disabilities, and traumatic brain injury, a vulnerable population that North Carolina's LME/MCOs are uniquely qualified to serve.

Markers of Atherosclerosis, Clinical Characteristics, and Treatment Patterns in Heart Failure: A Case-Control Study of Middle-Aged Adult Heart Failure Patients in Rural Kenya.

BACKGROUND: Although risk factors for heart failure are increasingly common worldwide, the contribution of atherosclerosis to heart failure in sub-Saharan Africa is largely unknown. OBJECTIVE: This study assessed the association between atherosclerotic risk factors and heart failure in a developing country. METHODS: We performed a case-control study of heart failure in rural Kenya. We assessed the risk factors for heart failure by using international criteria based on electrocardiogram (ECG), echocardiogram, physical examination findings, and laboratory testing. Atherosclerotic risk factors were determined by ECG, echocardiogram, ankle-brachial index (ABI), and lipid testing. We described the relationship of wall motion abnormalities on echocardiogram, ABI <0.9, and ischemic pattern on ECG with the presence of heart failure with multivariable logistic regression adjusting for age and sex and using adjusted odds ratios (AORs) and 95% confidence intervals (CIs). RESULTS: There were 125 cases and 191 controls (n = 316); 49% were male. The mean age was 60 (SD = 13) years. Most patients had hypertension (53%), and 16% had human immunodeficiency virus infection. Lipids were in the normal range for all. Cases were older than controls (62 years vs. 58 years, respectively). The most common abnormality associated with heart failure was dilated cardiomyopathy. Ischemic heart failure was the second most common cause in men. Cases were more likely to have an ABI <0.9 (46% vs. 31%; AOR: 1.99; 95% CI: 1.19 to 3.32), ischemia or infarct on ECG (68% vs. 43%; AOR: 3.01; 95% CI: 1.43 to 6.34), and wall motion abnormalities on echocardiogram (54% vs. 15%; AOR: 7.00; 95% CI: 3.95 to 12.39). CONCLUSIONS: Ischemic heart failure is more common in Kenya than previously recognized. Noninvasive markers of atherosclerosis are routinely found among patients with heart failure. Treatment and prevention of heart failure in sub-Saharan Africa must consider many causes including those related to atherosclerosis.

Building Sustainable Capacity for Cardiovascular Care at a Public Hospital in Western Kenya.

Cardiovascular disease deaths are increasing in low- and middle-income countries and are exacerbated by health care systems that are ill-equipped to manage chronic diseases. Global health partnerships, which have stemmed the tide of infectious diseases in low- and middle-income countries, can be similarly applied to address cardiovascular diseases. In this review, we present the experiences of an academic partnership between North American and Kenyan medical centers to improve cardiovascular health in a national public referral hospital. We highlight our stepwise approach to developing sustainable cardiovascular services using the health system strengthening World Health Organization Framework for Action. The building blocks of this framework (leadership and governance, health workforce, health service delivery, health financing, access to essential medicines, and health information system) guided our comprehensive and sustainable approach to delivering subspecialty care in a resource-limited setting. Our experiences may guide the development of similar collaborations in other settings.

Optimizing linkage and retention to hypertension care in rural Kenya (LARK hypertension study): study protocol for a randomized controlled trial.

BACKGROUND: Hypertension is the leading global risk factor for mortality. Hypertension treatment and control rates are low worldwide, and delays in seeking care are associated with increased mortality. Thus, a critical component of hypertension management is to optimize linkage and retention to care. METHODS/DESIGN: This study investigates whether community health workers, equipped with a tailored behavioral communication strategy and smartphone technology, can increase linkage and retention of hypertensive individuals to a hypertension care program and significantly reduce blood pressure among them. The study will be conducted in the Kosirai and Turbo Divisions of western Kenya. An initial phase of qualitative inquiry will assess facilitators and barriers of linkage and retention to care using a modified Health Belief Model as a conceptual framework. Subsequently, we will conduct a cluster randomized controlled trial with three arms: 1) usual care (community health workers with the standard level of hypertension care training); 2) community health workers with an additional tailored behavioral communication strategy; and 3) community health workers with a tailored behavioral communication strategy who are also equipped with smartphone technology. The co-primary outcome measures are: 1) linkage to hypertension care, and 2) one-year change in systolic blood pressure among hypertensive individuals. Cost-effectiveness analysis will be conducted in terms of costs per unit decrease in blood pressure and costs per disability-adjusted life year gained. DISCUSSION: This study will provide evidence regarding the effectiveness and cost-effectiveness of strategies to optimize linkage and retention to hypertension care that can be applicable to non-communicable disease management in low- and middle-income countries. TRIAL REGISTRATION: This trial is registered with (NCT01844596) on 30 April 2013.

Chronic noncommunicable cardiovascular and pulmonary disease in sub-Saharan Africa: an academic model for countering the epidemic.

Noncommunicable diseases are rapidly overtaking infectious, perinatal, nutritional, and maternal diseases as the major causes of worldwide death and disability. It is estimated that, within the next 10 to 15 years, the increasing burden of chronic diseases and the aging of the population will expose the world to an unprecedented burden of chronic diseases. Preventing the potential ramifications of a worldwide epidemic of chronic noncommunicable diseases in a sustainable manner requires coordinated, collaborative efforts. Herein, we present our collaboration's strategic plan to understand, treat, and prevent chronic cardiovascular and pulmonary disease (CVPD) in western Kenya, which builds on a 2-decade partnership between academic universities in North America and Kenya, the Academic Model Providing Access to Healthcare. We emphasize the importance of training Kenyan clinician-investigators who will ultimately lead efforts in CVPD care, education, and research. This penultimate aim will be achieved by our 5 main goals. Our goals include creating an administrative core capable of managing operations, develop clinical and clinical research training curricula, enhancing existing technology infrastructure, and implementing relevant research programs. Leveraging a strong international academic partnership with respective expertise in cardiovascular medicine, pulmonary medicine, and medical informatics, we have undertaken to understand and counter CVPD in Kenya by addressing patient care, teaching, and clinical research.

Improvement in health-related quality of life after hospitalization predicts event-free survival in patients with advanced heart failure.

BACKGROUND: Health-related quality of life (HRQOL) is a major clinical outcome for heart failure (HF) patients. We aimed to determine the frequency, durability, and prognostic significance of improved HRQOL after hospitalization for decompensated HF. METHODS AND RESULTS: We analyzed HRQOL, measured serially using the Minnesota Living with Heart Failure Questionnaire (MLHFQ), for 425 patients who survived to discharge in a multicenter randomized clinical trial of pulmonary artery catheter versus clinical assessment to guide therapy for patients with advanced HF. All patients enrolled had 1 or more prior HF hospitalizations or chronic high diuretic doses and 1 or more symptom and 1 sign of fluid overload at admission. Improvement, defined as a decrease of more than 5 points in MLHFQ total score, occurred in 68% of patients by 1 month and stabilized. The degree of 1-month improvement differed (P < .0001 group x time interaction) between 6-month survivors and non-survivors. In a Cox regression model, after adjustment for traditional risk factors for HF morbidity and mortality, improvement in HRQOL by 1 month compared to worsening at 1 month or no change predicted time to subsequent event-free survival (P=.013). CONCLUSIONS: In patients hospitalized with severe HF decompensation, HRQOL is seriously impaired but improves substantially within 1 month for most patients and remains improved for 6 months. Patients for whom HRQOL does not improve by 1 month after hospital admission merit specific attention both to improve HRQOL and to address high risk for poor event-free survival.

Association of weight change with subsequent outcomes in patients hospitalized with acute decompensated heart failure.

The association of weight loss achieved through various decongestive strategies with clinical outcomes in patients with acute decompensated heart failure (HF) is not well described. The aim of this study was to determine the relation between weight change during hospitalization and subsequent clinical events in patients with decompensated HF. Data from 433 patients hospitalized with advanced HF enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial were evaluated. The influence of change in weight during hospitalization to clinical outcomes (days alive out of the hospital in the first 6 months; death; death or rehospitalization; and death, rehospitalization, or cardiac transplantation) was evaluated. On average, patients lost approximately 3.6 kg during hospitalization. When categorized into 3 weight loss tertiles, those in the highest tertile were more likely to be older, women, and smokers, with higher body weights, previous percutaneous coronary interventions, baseline heart rates, and brain natriuretic peptide and blood urea nitrogen values but lower ejection fractions and peak oxygen consumption. No significant differences were observed between weight change and any in-hospital or follow-up events (days well: hazard ratio 0.995, 95% confidence interval 0.975 to 1.016; 180-day death: hazard ratio 1.012, 95% confidence interval 0.969 to 1.057; death or rehospitalization at 180 days: hazard ratio 1.014, 95% confidence interval 0.990 to 1.038). In conclusion, weight loss in patients with acute decompensated HF during hospitalization was not related to clinical end points. These data challenge the merit of using weight as a surrogate end point for more important clinical events (i.e., death and/or rehospitalization) in patients with HF in the design of treatment strategies for novel therapeutic agents in randomized controlled clinical trials.

High mortality without ESCAPE: the registry of heart failure patients receiving pulmonary artery catheters without randomization.

BACKGROUND: In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), there was no difference in days alive and out of the hospital for patients with decompensated heart failure randomly assigned to therapy guided by pulmonary artery catheter (PAC) plus clinical assessment versus clinical assessment alone. The external validity of these findings is debated. METHODS AND RESULTS: ESCAPE sites enrolled 439 patients receiving PAC without randomization in a prospective registry. Baseline characteristics, pertinent trial exclusion criteria, reasons for PAC use, hemodynamics, and complications were collected. Survival was determined from the National Death Index and the Alberta Registry. On average, registry patients had lower blood pressure, worse renal function, less neurohormonal antagonist therapy, and higher use of intravenous inotropes compared with trial patients. Although clinical assessment anticipated less volume overload and greater hypoperfusion among the registry population, measured filling pressures were similarly elevated in the registry and trial patients, whereas measured perfusion was slightly higher among registry patients. Registry patients had longer hospitalization (13 vs 6 days, P < .001) and higher 6-month mortality (34% vs 20%, P < .001) than trial patients. CONCLUSIONS: The decision to use PAC without randomization identified a population with higher disease severity and risk of mortality. This prospective registry highlights the complex context of patient selection for randomized trials.

Rapid assay brain natriuretic peptide and troponin I in patients hospitalized with decompensated heart failure (from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness Trial).

Rapid-assay biomarkers may predict outcomes in patients with decompensated heart failure (HF). This study assessed whether rapid-assay B-type natriuretic peptide (BNP) and troponin I predicts length of stay and mortality and correlates with pulmonary artery catheter (PAC)-derived hemodynamics in patients hospitalized with acute HF. There were 141 nonconsecutive patients in this prospective cohort study of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), a randomized trial testing PACs in 433 patients with severe decompensated HF. Biomarkers were drawn at baseline and discharge and when the first, second, and final hemodynamics were obtained in 69 patients randomly assigned to PACs. Cox analysis was used to model mortality, length of stay, and rehospitalization, and Pearson's correlations were used to describe the relation among BNP, troponin I, and PAC-derived hemodynamics. The median (25th percentile, 75th percentile) BNP levels were 783 pg/ml (329, 1,565) at baseline and 468 pg/ml (240, 946) at discharge. After treatment for HF, the median BNP level decreased by 144 pg/ml (-653, 55; p = 0.004). Patients with baseline BNP levels >1,500 pg/ml had greater mortality at 6 months and almost twice the length of stay as patients with BNP levels <500 pg/ml (10.1 vs 5.7 days, p = 0.002). Troponin I did not predict these outcomes. First BNP correlated modestly with first right atrial pressure (r = 0.47, p = 0.005) and first pulmonary capillary wedge pressure (r = 0.54, p = 0.001). Final BNP correlated modestly with final right atrial pressure (r = 0.63, p = 0.001). In conclusion, patients with BNP >1,500 pg/ml had greater mortality and longer length of stay than patients with BNP <500 pg/ml. BNP decreased after hospitalization, but correlated modestly with PAC-derived hemodynamics. Rapid-assay BNP may provide information that helps physicians decide when to pursue more aggressive and invasive therapies.

Prediction of rehospitalization and death in severe heart failure by physicians and nurses of the ESCAPE trial.

BACKGROUND: The predictive accuracy of physician investigators and nurse coordinators in estimating the risk of rehospitalization and death was determined for 373 hospitalized patients with severe advanced heart failure enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial. METHODS AND RESULTS: Estimates were made at discharge, and patients were followed for 6 months after hospitalization. A statistical prognostic model was developed from clinical and laboratory data for the end points of rehospitalization and death. Both nurse and physician predictions of death were generally associated with the observed deaths (c-indices of 0.675 and 0.611), although the nurses' prediction was significantly better (chi-square = 4.75, P = .029). The prediction ability of the prognostic model was similar to the physicians' model (c-index = 0.603). The predictions of rehospitalization were much weaker for nurse, physician and prognostic models. CONCLUSIONS: Nurses' estimations of survival in discharged, advanced-stage heart failure patients were superior to either physicians' or model-based predictions. Not nurses, physicians, or the prognostic model provided useful predictions for rehospitalizations, but this may have resulted from the fact that the rehospitalization estimates did not include the death risk.

Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure.

BACKGROUND: Treatment of decompensated heart failure often includes the use of intravenous vasoactive medications, but the effect on outcome has not been clearly defined. METHODS: Data from 433 patients enrolled in the ESCAPE trial were analyzed to determine 6-month risks of all-cause mortality and all-cause mortality plus rehospitalization associated with the use of vasodilators, inotropes, and their combination. Patients had a mean left ventricular ejection fraction of 19%, 6-minute walk distance of 414 ft, and systolic blood pressure of 106 mm Hg. The main outcome measure was multivariable risk-adjusted 6-month hazard ratios (HRs). RESULTS: Overall 6-month mortality was 19%. Risk-adjusted HRs were not statistically significant for vasodilators (1.39, 95% CI 0.64-3.00), but were significant for inotropes (2.14, 95% CI 1.10-4.15) and the combination (4.81, 95% CI 2.34-9.90). Risk-adjusted 6-month mortality plus rehospitalization HRs were not significant for vasodilators (1.20, 95% CI 0.81-1.78, P = .37), but were significant for inotropes (1.96, 95% CI 1.37-2.82, P < .001) and their combination (2.90, 95% CI 1.88-4.48, P = .001). The decision to use vasodilators or inotropes was determined by hemodynamic parameters and renal function, but the main factor was treatment site. CONCLUSIONS: In ESCAPE, the choice of medications was mainly determined by the treatment site. Use of inotropic agents was associated with adverse outcomes, whereas the use of vasodilators was not. Inotropes in combination with vasodilators identified a group with the highest mortality. Prospective studies are needed to establish the appropriate use of vasoactive medications in this population.

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.

CONTEXT: Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. OBJECTIVE: To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. DESIGN, SETTING, AND PARTICIPANTS: The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. MAIN OUTCOME MEASURES: The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. RESULTS: Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. CONCLUSIONS: Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.

Impact of the pulmonary artery catheter in critically ill patients: meta-analysis of randomized clinical trials.

CONTEXT: Randomized clinical trials (RCTs) evaluating the pulmonary artery catheter (PAC) have been limited by small sample size. Some nonrandomized studies suggest that PAC use is associated with increased morbidity and mortality. OBJECTIVE: To estimate the impact of the PAC device in critically ill patients. DATA SOURCES: MEDLINE (1985-2005), the Cochrane Controlled Trials Registry (1988-2005), the National Institutes of Health ClinicalTrials.gov database, and the US Food and Drug Administration Web site for RCTs in which patients were randomly assigned to PAC or no PAC were searched. Results from the ESCAPE trial of patients with severe heart failure were also included. Search terms included pulmonary artery catheter, right heart catheter, catheter, and Swan-Ganz. STUDY SELECTION: Eligible studies included patients who were undergoing surgery, in the intensive care unit (ICU), admitted with advanced heart failure, or diagnosed with acute respiratory distress syndrome and/or sepsis; and studies that reported death and the number of days hospitalized or the number of days in the ICU as outcome measures. DATA EXTRACTION: Information on eligibility criteria, baseline characteristics, interventions, outcomes, and methodological quality was extracted by 2 reviewers. Disagreements were resolved by consensus. DATA SYNTHESIS: In 13 RCTs, 5051 patients were randomized. Hemodynamic goals and treatment strategies varied among trials. A random-effects model was used to estimate the odds ratios (ORs) for death, number of days hospitalized, and use of inotropes and intravenous vasodilators. The combined OR for mortality was 1.04 (95% confidence interval [CI], 0.90-1.20; P = .59). The difference in the mean number of days hospitalized for PAC minus the mean for no PAC was 0.11 (95% CI, -0.51 to 0.74; P = .73). Use of the PAC was associated with a higher use of inotropes (OR, 1.58; 95% CI, 1.19-2.12; P = .002) and intravenous vasodilators (OR, 2.35; 95% CI, 1.75-3.15; P<.001). CONCLUSIONS: In critically ill patients, use of the PAC neither increased overall mortality or days in hospital nor conferred benefit. Despite almost 20 years of RCTs, a clear strategy leading to improved survival with the PAC has not been devised. The neutrality of the PAC for clinical outcomes may result from the absence of effective evidence-based treatments to use in combination with PAC information across the spectrum of critically ill patients.

Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial.

CONTEXT: Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. OBJECTIVE: To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. DESIGN AND SETTING: Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. PARTICIPANTS: Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. INTERVENTIONS: Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. MAIN OUTCOME MEASURES: Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. RESULTS: On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. CONCLUSION: This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.