Daniel J. Crusan

Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis

Background: It is unclear if all patients with relapsing–remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent. Some forms of progressive MS (e.g. primary progressive MS (PPMS)) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age at progression onset between secondary progressive MS (SPMS) and PPMS but may introduce unclear biases. Objective: Our aim is to confirm that onset of progressive disease course is more relevant to the patient’s age than the presence or duration of a pre-progression relapsing disease course in MS. Methods: We studied a population-based MS cohort (n=210, RRMS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary (PPMS; n=322), single attack (SAPMS; n=112) and secondary progressive (SPMS; n=421). We studied demographics (chi2 or t-test), age-of-progression-onset (t-test) and time to Expanded Disability Status Scale of 6 (EDSS6) (Kaplan–Meier analyses). Results: Sex ratio (p=0.58), age at progression onset (p=0.37) and time to EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age at progression onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression. Conclusions: Patients with RRMS do not inevitably develop a progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.

Development and validation of a risk score to predict early mortality in recipients of implantable cardioverter-defibrillators.

BACKGROUND Current guidelines do not recommend implantable cardioverter-defibrillator (ICD) implantation in patients with a life expectancy of <1 year. Better methods are needed for identifying patients at high risk for early mortality despite ICD therapy. OBJECTIVE To develop and validate a risk prediction score to identify patients at high risk for death within 1 year despite ICD therapy. DESIGN Detailed clinical data were collected on a large observational cohort of ICD patients from 3 tertiary care centers. One-third of the patients were randomly selected to form the prediction group (PG) from which a risk score was developed using logistic regression. This score was then applied to the remaining two-thirds of the cohort (validation group [VG]) to assess the risk scores predictive accuracy. RESULTS The total cohort included 2717 ICD patients (mean age = 64.6 ± 14.5, male = 77.2%, primary prevention = 74.7%). A simple risk score incorporating peripheral arterial disease, age ≥ 70 years, creatinine ≥ 2.0 mg/dL, and ejection fraction ≤20% (PACE) accurately predicted 1-year mortality in the VG. Patients with a risk score of ≥3 had a >4-fold excess 1-year mortality compared with patients with a risk score of <3 (16.5% vs 3.5%; P <.0001). LIMITATION Risk reduction provided by ICD therapy in this cohort is not known given the lack of a control group. CONCLUSIONS A simple risk score accurately predicts 1-year mortality in ICD patients, as patients with a PACE risk score of ≥3 are at high risk despite ICD therapy.

Relapses and disability accumulation in progressive multiple sclerosis

Objective: We examined the effect of relapses—before and after progression onset—on the rate of postprogression disability accrual in a progressive multiple sclerosis (MS) cohort. Methods: We studied patients with primary progressive MS (n = 322) and bout-onset progressive MS (BOPMS) including single-attack progressive MS (n = 112) and secondary progressive MS (n = 421). The effect of relapses on time to Expanded Disability Status Scale (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint. Results: Preprogression relapses (hazard ratio [HR]: 1.63; 95% confidence interval [CI]: 1.34–1.98), postprogression relapses (HR: 1.37; 95% CI: 1.11–1.70), female sex (HR: 1.19; 95% CI: 1.00–1.43), and progression onset after age 50 years (HR: 1.47; 95% CI: 1.21–1.78) were associated with shorter time to EDSS 6. Postprogression relapses occurred in 29.5% of secondary progressive MS, 10.7% of single-attack progressive MS, and 3.1% of primary progressive MS. Most occurred within 5 years (91.6%) after progressive disease onset and/or before age 55 (95.2%). Immunomodulation after onset of progressive disease course (HR: 0.64; 95% CI: 0.52–0.78) seemingly lengthened time to EDSS 6 (for BOPMS with ongoing relapses) when analyzed as a dichotomous variable, but not as a time-dependent variable. Conclusions: Pre- and postprogression relapses accelerate time to severe disability in progressive MS. Continuing immunomodulation for 5 years after the onset of progressive disease or until 55 years of age may be reasonable to consider in patients with BOPMS who have ongoing relapses.

Impact of Implanted Recalled Sprint Fidelis Lead on Patient Mortality

OBJECTIVES This study sought to compare all-cause mortality in patients with Fidelis leads (Medtronic, Minneapolis, Minnesota) to those with a nonadvisory lead. BACKGROUND Although Fidelis leads are prone to fracture, and rare deaths due to lead failure have been reported, it is unclear whether the presence of a Fidelis lead is associated with increased mortality. This study compares all-cause mortality in a large cohort of patients with Fidelis and Quattro implantable cardioverter-defibrillator (ICD) leads. METHODS All patients with Fidelis (Medtronic models 6931, 6948, and 6949) and Quattro (Medtronic model 6947) leads followed at 3 tertiary care centers were identified from the medical records (implant dates: November 19, 2001, to December 23, 2008). Clinical and device-specific data were collected into a common database. Deaths were identified from medical records and the Social Security Death Index. Survival was estimated using the Kaplan-Meier method. RESULTS A total of 2,671 patients (1,030 Fidelis and 1,641 Quattro) were identified. There were 398 deaths: 147 in the Fidelis group (mean follow-up: 34.4 months) and 251 in the Quattro group (mean follow-up: 39.9 months). No deaths were associated with 85 Fidelis and 23 Quattro failures. At 4 years, survival was diminished in patients with Fidelis compared with Quattro leads (80.7% vs. 83.9%, p = 0.025). After adjustment for factors associated with mortality, survival was similar between groups. One hundred percent pacing was not associated with mortality. Elective removal of nonfailed leads was performed in 5.1% of Fidelis and 0.9% of Quattro patients. CONCLUSIONS In a conservatively managed cohort, in whom observation was predominantly utilized, adjusted survival is similar between patients with Fidelis and Quattro ICD leads.

The association of active cancer with venous thromboembolism location: a population-based study.

OBJECTIVE To test active cancer for an association with venous thromboembolism (VTE) location. PATIENTS AND METHODS Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN, residents with incident VTE during the 35-year period 1966-2000 (N = 3385). We restricted analyses to residents with objectively diagnosed VTE during the 17-year period from January 1, 1984, to December 31, 2000 (N = 1599). For each patient, we reviewed the complete medical records in the community for patient age, gender, and most recent body mass index at VTE onset; VTE event type and location; and previously identified independent VTE risk factors (ie, surgery, hospitalization for acute medical illness, active cancer, leg paresis, superficial venous thrombosis, and varicose veins). Using logistic regression we tested active cancer for an association with each of 4 symptomatic VTE locations (arm or intra-abdominal deep venous thrombosis [DVT], intra-abdominal DVT, pulmonary embolism, and bilateral leg DVT), adjusted for age, gender, body mass index, and other VTE risk factors. RESULTS In multivariate analyses, active cancer was independently associated with arm or intra-abdominal DVT (odds ratio [OR], 1.76; P = .01), intra-abdominal DVT (OR, 2.22; P = .004), and bilateral leg DVT (OR, 2.09; P = .02), but not pulmonary embolism (OR, 0.93). CONCLUSION Active cancer is associated with VTE location. Location of VTE may be useful in decision making regarding cancer screening.

Incidence of venous thromboembolism after elective knee arthroscopic surgery: a historical cohort study

The incidence of symptomatic venous thromboembolism (VTE) after knee arthroscopy is uncertain.

Reasons for the persistent incidence of venous thromboembolism

Reasons for trends in venous thromboembolism (VTE) incidence are uncertain. It was our objective to determine VTE incidence trends and risk factor prevalence, and estimate population-attributable risk (PAR) trends for each risk factor. In a population-based cohort study of all residents of Olmsted County, Minnesota from 1981-2010, annual incidence rates were calculated using incident VTE cases as the numerator and age- and sex-specific Olmsted County population estimates as the denominator. Poisson regression models were used to assess the relationship of crude incidence rates to year of diagnosis, age at diagnosis, and sex. Trends in annual prevalence of major VTE risk factors were estimated using linear regression. Poisson regression with time-dependent risk factors (person-years approach) was used to model the entire population of Olmsted County and derive the PAR. The age- and sex-adjusted annual VTE incidence, 1981-2010, did not change significantly. Over the time period, 1988-2010, the prevalence of obesity, surgery, active cancer and leg paresis increased. Patient age, hospitalisation, surgery, cancer, trauma, leg paresis and nursing home confinement jointly accounted for 79 % of incident VTE; obesity accounted for 33 % of incident idiopathic VTE. The increasing prevalence of obesity, cancer and surgery accounted in part for the persistent VTE incidence. The PAR of active cancer and surgery, 1981-2010, significantly increased. In conclusion, almost 80 % of incident VTE events are attributable to known major VTE risk factors and one-third of incident idiopathic VTE events are attributable to obesity. Increasing surgery PAR suggests that concurrent efforts to prevent VTE may have been insufficient.

Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis

Objective: To evaluate the relationship between early relapse recovery and onset of progressive multiple sclerosis (MS). Methods: We studied a population-based cohort (105 patients with relapsing-remitting MS, 86 with bout-onset progressive MS) and a clinic-based cohort (415 patients with bout-onset progressive MS), excluding patients with primary progressive MS. Bout-onset progressive MS includes patients with single-attack progressive and secondary progressive MS. “Good recovery” (as opposed to “poor recovery”) was assigned if the peak deficit of the relapse improved completely or almost completely (patient-reported and examination-confirmed outcome measured ≥6 months post relapse). Impact of initial relapse recovery and first 5-year average relapse recovery on cumulative incidence of progressive MS was studied accounting for patients yet to develop progressive MS in the population-based cohort (Kaplan-Meier analyses). Impact of initial relapse recovery on time to progressive MS onset was also studied in the clinic-based cohort with already-established progressive MS (t test). Results: In the population-based cohort, 153 patients (80.1%) had on average good recovery from first 5-year relapses, whereas 30 patients (15.7%) had on average poor recovery. Half of the good recoverers developed progressive MS by 30.2 years after MS onset, whereas half of the poor recoverers developed progressive MS by 8.3 years after MS onset (p = 0.001). In the clinic-based cohort, good recovery from the first relapse alone was also associated with a delay in progressive disease onset (p < 0.001). A brainstem, cerebellar, or spinal cord syndrome (p = 0.001) or a fulminant relapse (p < 0.0001) was associated with a poor recovery from the initial relapse. Conclusions: Patients with MS with poor recovery from early relapses will develop progressive disease course earlier than those with good recovery.

Effect of a near-universal hospitalization-based prophylaxis regimen on annual number of venous thromboembolism events in the US

The annual number of US venous thromboembolism (VTE) events, the number of potentially preventable events, and the effect of hospitalization-based prophylaxis are uncertain. We estimated VTE attack (incident plus recurrent VTE) rates and the total annual number of US VTE events related and unrelated to hospitalization using Rochester Epidemiology Project resources to identify all Olmsted County, Minnesota, residents with incident or recurrent VTE over the 6-year period 2005-2010. The average annual VTE attack rates related and unrelated to hospitalization were 282 and 8 per 10 000 person-years, respectively. The estimated average number of US VTE events was 495 669 per year (48% unrelated to hospitalization). Among Olmsted County residents hospitalized at a Mayo Clinic hospital from 2005 to 2010, the proportion of patients receiving VTE prophylaxis or with an indication that prophylaxis was unnecessary increased from ∼40% in 2005 to ∼90% by 2010. The annual age- and sex-adjusted hospitalization-related (in-hospital) VTE attack rates from 2005 to 2010 ranged from 251 to 306 (1155 to 1751) per 10 000 person-years (bed-years) and did not change significantly. The median durations of hospitalization and in-hospital prophylaxis were 3 days and 70 hours, respectively. A total of 75% of VTE events occurred after hospital discharge, with a 19.5-day median time to VTE. Additional efforts are needed to identify the individual inpatient and outpatient at high risk for incident and recurrent VTE and target (longer duration) primary and secondary prophylaxis to high-risk individuals who would benefit most.

Relation between fractional flow reserve value of coronary lesions with deferred revascularization and cardiovascular outcomes in non-diabetic and diabetic patients

BACKGROUND FFR of deferred PCI lesions can predict future cardiovascular events. However, the prognostic utility of FFR remains unclear in diabetic patients in view of the potential impact of the diffuse nature of vascular disease process. We aimed to study the relation between fractional flow reserve (FFR) values and long-term outcomes of diabetic and non-diabetic patients with deferred percutaneous coronary intervention (PCI). METHODS Patients with FFR assessment and deferred PCI (n=630) were enrolled and stratified according to diabetes mellitus (DM) status and FFR values. Patients were followed over a median of 39months. Cox proportional hazard regression models were used to analyze the association between clinical endpoints and clinical factors such as DM and FFR. RESULTS In non-diabetics (n=450), higher FFR values were associated with less cardiovascular events (hazard ratio (HR) for death and myocardial infarction (MI) [95% confidence interval (CI)], 0.61[0.44 to 0.86] per 0.1 increase in FFR, p=0.007; HR for revascularization [95%CI], 0.66[0.49 to 0.9] per 0.1 increase in FFR, p=0.006). In diabetics (n=180), there was no difference in death and MI across the range of FFR values. Among those patients with an FFR >0.85, diabetics had a more than two-fold higher risk of death and MI than non-diabetics (HR [95% CI], 2.20 [1.19 to 4.01], p=0.015). CONCLUSION Among non-diabetic patients with deferred PCI, a higher FFR was associated with lower rates of death, MI and revascularization. On the contrary in diabetic patients with deferred revascularization, FFR was not able to differentiate the risk of cardiovascular events.