Clinical Briefs in Primary Care

Extended Treatment of VTE with Dabigatran vs Warfarin

Source: Schulman S, et al. N Engl J Med 2013;368:709-718.

Current recommendations for treatment of uncomplicated venous thromboembolism (VTE) in the absence of persistent risk factors for recurrence (e.g., protein C, protein S deficiency) suggest at least 3 months of antithrombotic therapy, typically with warfarin. Risk of recurrence, however, is not insubstantial, and recent clinical trials have shown that extending the duration of antithrombotic therapy after a course of warfarin (with aspirin, for instance) reduces the risk for recurrent VTE.

When warfarin is used for extended VTE recurrence prophylaxis, serious bleeding risk is about 1% annually. In comparison trials to warfarin, major bleeding rates on dabigatran have been generally comparable to warfarin, and intracerebral bleeding was demonstrably less with dabigatran than warfarin. Since dabigatran does not require monitoring, monthly physician visits, or dietary modulation, and has infrequent potential for drug interaction, it provides an attractive alternative.

Schulman et al report the results of two randomized, controlled, double-blind trials of dabigatran 150 mg twice daily vs warfarin or placebo in patients who had completed at least 3 months of warfarin treatment. Dabigatran was found to be noninferior to warfarin for prevention of recurrent VTE, with less frequent bleeding than warfarin (0.9% vs 1.8%). Dabigatran may be a viable alternative for extending DVT prophylaxis after a "traditional" course of warfarin.

Selection Criteria for Lung Cancer Screening

Source: Tammemagi M, et al. N Engl J Med 2013;368:728-736.

The national lung screening trial (NLST) reported in 2011 that low-dose CT screening in selected smokers (n = 53,454) reduced mortality from lung cancer by 20%. Entry criteria for the NLST included age 55-74 years with at least a 30 pack-years smoking history (former smokers, if they had quit within the last 15 years, were also enrolled). Subsequently, national organizations have variously endorsed lung cancer screening for persons matching NLST eligibility criteria.

The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) developed a lung-cancer risk prediction model based on 154,901 subjects. The PLCO determined other predictors of lung cancer beyond age and smoking duration used in the NLST, including body mass index, family history of lung cancer, and presence of chronic obstructive pulmonary disease. Because the PLCO duration of follow-up was longer than NLST (9.2 years vs 6.5 years), the strength of the PLCO prediction model might be anticipated to be greater than NLST.

A comparison between the NLST and PLCO prediction models found that the PLCO criteria had greater sensitivity and specificity, ultimately missing 43% fewer lung cancers than NLST. The PLCO prediction model has the potential to improve outcomes for persons at risk of lung cancer.

Special Subgroups in Hypertension: Obese Hypertensives

Source: Weber MA, et al. Lancet 2013; 381:537-545.

The inter-relatedness of obesity, hypertension, and cardiovascular (CV) events is complex. Obesity is independently associated with high blood pressure, all-cause mortality, and CV mortality. Yet, some reports have suggested that when parsing out CV events among a secondary prevention population (persons with existing CV disease), subjects with normal body weight bear a disproportionately greater risk than overweight and obese persons.

To further clarify this counterintuitive knowledge base, Weber et al report on an analysis of the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension trial (ACCOMPLISH). ACCOMPLISH was performed to determine the relative efficacy of an angiotensin-converting enzyme (ACE) inhibitor + hydrochlorothiazide (HCTZ) vs ACE + amlodipine (CCB) in patients (n = 11,506) with Stage 2 hypertension (blood pressure > 160 mmHg). The trial ultimately demonstrated that ACE + CCB provided a significant mortality advantage over ACE + HCTZ.

In this report, ACCOMPLISH study subjects were divided into normal weight (body mass index [BMI] < 25), overweight (BMI 25-29), and obese categories (≥ BMI 30). CV events were most frequent in the normal weight group, and least frequent in the obese patients in the ACE + HCTZ arm of the trial. In the ACE + CCB arm, there were no differences between weight categories in outcomes.

The seemingly paradoxical relationship between overweight and outcomes in persons with established CV disease (myocardial infarction, cerebrovascular accident, or existing hypertension) is difficult to explain. It may be that obesity-related hypertension is mediated by a different, more benign pathophysiology, hence producing more favorable outcomes, although this concept has been insufficiently explored. Finally, because of relatively higher event rates with ACE + HCTZ in normal-weight patients, clinicians should select ACE + CCB since event reduction is equivalent across weight groups for this combination.

Omalizumab for Asthma in Real Life

Source: Grimaldi-Bensouda L, et al. Chest 2013;143:398-405.

In evidence-based medicine terminology, "efficacy" is the term used to reflect results achieved within a clinical trial, whereas "effectiveness" indicates the results seen in "typical practice settings," commonly called "real-life settings." Clinical trials are anticipated to provide results superior to those in practice settings, where patients cannot be so readily de-selected or excluded, where resources may be more limited, and where rigorous regimentation for administration of treatment is less abundant.

Omalizumab (OMA) is not generally regarded as a first-line asthma medication, but rather an appropriate add-on when guideline-based foundation therapies (inhaled steroids, long-acting beta agonists, and leukotriene receptor antagonists) are insufficient to provide control. Although only 30-50% of asthmatics have a prominent underlying allergic component, among difficult-to-control asthmatics, the number may be as high as 80%. Clinical trials indicate that OMA, by blocking IgE, is a useful add-on in such resistant asthma cases. But do "real-life" settings reflect similar benefit?

Grimaldi-Bensouda et al report on refractory asthma patients (n = 767) recruited by more than 100 physicians who prescribed OMA as an add-on treatment. During a follow-up period of almost 2 years, study subjects who received any doses of OMA enjoyed a 43% relative risk reduction in likelihood of hospitalization or emergency department visits for asthma. Subjects on treatment with OMA demonstrated an even greater benefit: 60% relative risk reduction.

In real-life settings, OMA provides substantial improvement in clinically important endpoints for patients with difficult-to-treat asthma.

Tenofovir: New Hope for Hepatitis B Patients

Source: Marcellin P, et al. Lancet 2013; 381:468-475.

Hepatitis B (HEP-B) is responsible for approximately half of hepatic carcinoma cases worldwide. While HEP-B treatment has been shown to reduce risk for liver failure and hepatic cancer in cirrhosis, whether currently available antiviral therapies actually reverse the underlying disease process is less well studied. Indeed, previous prevailing wisdom had opined that the fibrotic changes of cirrhosis might not be amenable to attempts at regression.

Tenofovir (TFV) is a potent HEP-B polymerase/reverse transcriptase inhibitor. Marcellin et al report on the results of an open-label trial of TFV in patients who had completed a 48-week antiviral treatment with either adefovir or TFV. Subjects were subsequently assigned to once-daily TFV for up to 7 years. Approximately one-fourth of patients had cirrhosis at baseline, and all subjects agreed to follow-up liver biopsy in the fifth year of the trial (240 weeks).

TFV was well tolerated and confirmed to be associated with regression of fibrosis (in the cirrhosis group) and improvement in liver histology (in the non-cirrhosis group) at 240 weeks. This large dataset is very supportive of a role for TFV not just in arresting disease progression, but actually in regression of cirrhosis.

H. pylori: Frequency of Recurrence After Successful Eradication

Source: Morgan DR. JAMA 2013;309: 578-586.

Worldwide, helicobacter pylori appears to be responsible for the majority of cases of gastric cancer. A Chinese clinical trial of H. pylori eradication through pharmacotherapy noted an almost 40% reduction in gastric cancer over the subsequent 15-year observation period. Initial eradication of H. pylori provides important risk reduction. Of course, initial treatment is sometimes not effective, and even when initial treatment is effective, there is potential for recurrence.

From a population of study subjects (n = 1091) cleared of H. pylori (confirmed by post-treatment negative urea breath tests), only 125 evidenced recurrence over a 1-year follow-up (11.5%). Factors associated with recurrence included non-adherence to H. pyloritreatment regimens and methodology of the treatment regimen (i.e., 14-day triple therapy, sequential therapy, or concomitant therapy, with sequential therapy being most successful). These recurrence rates are typical of low-income countries, whereas recurrence rates are as much as 30% less in high-income countries. Overall, H. pylori treatment is well tolerated, provides important risk reduction for gastric cancer, and is associated with few recurrences that can be managed by appropriate retreatment.