2008 (part 2)

Robert K. Cato, MD Assistant Professor of Clinical Medicine Chief, Division of General Internal Medicine Penn Presbyterian Medical Center University of Pennsylvania School of Medicine Philadelphia, PA

Jack Ende, MD Professor of Medicine Chief, Department of Medicine Penn Presbyterian Medical Center University of Pennsylvania School of Medicine Philadelphia, PA

 

 

 

 

To determine whether medical therapy with α-blockers and calcium channel blockers (medical expulsive therapy) is effective in hastening the passage of ureteral calculi.

 

A systematic review and meta-analysis including 211 studies yielded 22 randomized trials involving nearly 2000 adult patients with radiographically confirmed ureteral calculi, to evaluate the benefit of α-antagonist (tamsulosin) and/or calcium channel blocker (nifedipine) compared with standard therapy. 

 

While none of the included studies met all the criteria for a well done randomized control trial, the authors used the techniques of influence analysis to assure that no single study unduly influenced the results. For the α-antagonist, tamsulosin, benefit was found in terms of likelihood of stone expulsion at 4 weeks (RR 1.59; 95% CI 1.44 to 1.75) with a number needed to treat of 3.3 (95% CI 2.1 to 4.5). For the trials that reported time to expulsion, a 2-to 6-day average improvement was found. For the calcium channel blocker nifedipine, stone expulsion rates were superior to standard therapy (RR 1.50; 95% CI 1.35 to 1.68) with an NNT of 3.9 (95% CI 3.2 to 4.6). Time to expulsion was improved in 7 of the 9 nifedipine trials. Minimal or no adverse side effects of either the tamsulosin (.4 mg/day) or nifedipine (30 mg/day) were observed.

 

The results of this study were concordant with another recent meta-analysis and suggest benefit from medical expulsive treatment for patients with ureteral stones ≥ 5 mm (but < 10 mm) in terms of stone passage, both in terms of likelihood and time to passage. The implication here is that patients treated with medical expulsive therapy experience fewer days of renal colic, and are less likely to require interventions such as lithotripsy or ureteroscopic procedures.

 

The lifetime risk of urolithiasis in the USA is estimated at 13% for men and 7% for women, with a recurrence rate of 50% within 5 years, accounting for 2 million office visits nationwide. Most ureteral calculi less than 5 mm in diameter pass spontaneously within 4 weeks of symptom onset. Persistent ureteral stones are associated with strictures and renal damage. For the most part, open surgery to remove stones has given way to less invasive methods including shock wave lithotripsy, ureteroscopy and percutaneous nephrolithotomy. These procedures, however, are expensive and not without morbidity. 

 

Insofar as ureteral contraction is driven by an increase in intercellular calcium and is modulated by the autonomic nervous system, and both α-antagonist and calcium channel blockers have been shown to inhibit ureteral spasm, it makes sense that these agents promote antegrade stone passage. Even more important is that this meta-analysis suggests the benefits of these well-tolerated drugs outweigh the risks. Recognizing the caveats associated with treatment decisions based upon meta-analyses, for patients with ureteral stones between 5 and 10 mm that are not passing quickly it makes sense to employ treatment with α adrenergic or calcium channel blockers for a period of about 4 weeks to promote stone passage and to avoid more uncomfortable and costly procedures. 

 

 

 

 

 

 

To determine whether a quadrivalent HPV vaccine will reduce cervical cancer and its precursor lesions (CIN 2 and 3).

 

This was a randomized, placebo-controlled double-blind study done in 90 centers in 16 countries worldwide. Over 12,000 women ages 15-26 were enrolled in the study, and received either the vaccine (quadrivalent, against HPV 6,11, 16 and 18) or placebo, given on day 1, month 2 and month 6 of the study. Subjects could not be pregnant or have a history of abnormal Pap smears prior to the study. Subjects had cervical Pap smear testing and viral HPV DNA testing done on various anogenital sites at baseline, and these were repeated periodically over four years. Pap smear and viral DNA analysis were done in double-blind fashion, and WHO reporting criteria were used. The primary endpoint was occurrence of CIN 2, CIN 3, or adenocarcinoma of the cervix (in situ or invasive).

 

cervical lesions as compared to placebo.

 

 

However, the authors also did an intention to treat analysis, which included all patients who were enrolled and randomized, including those with baseline cervical abnormalities or HPV infection. The overall risk of HPV 16 or 18 infection and cervical changes in patients receiving the vaccine was still reduced, but less so (1.6% developed vaccine type HPV related CIN 2 or 3 or adenocarcinoma, vs. 3.2% in placebo, about 50% effective). In addition, the risk of CIN (2 or 3) or adenocarcinoma, irrespective of HPV subtype, was 4.6% for vaccinated group, vs. 5.7% in the placebo group, or about 17% effective. Only the incidence of CIN 2 was significantly reduced in the treatment group; there was no difference in CIN 3 or adenocarcinoma in situ risk. 

 

For patients who had baseline cervical changes or were HPV 16 or 18 positive, the vaccine was ineffective: there were no differences in subsequent cervical lesions between vaccination and placebo groups. In patients who became pregnant during the study, there were no differences in birth outcomes, though the study was not designed or powered to carefully study this issue.

 

Vaccination with a quadrivalent HPV vaccine, when properly administered to women who do not have HPV infections or cervical changes at baseline, is highly effective (99%) at reducing future HPV infections and significant cervical changes (CIN 2 or 3) associated with those specific HPV subtypes. For the mean three years of follow-up, there was no difference in the risk of adenocarcinoma, though this is probably too short a time to detect such a difference. The HPV vaccination was only moderately effective (about 17%) at reducing new cervical changes overall, regardless of HPV subtype infections, and there is no evidence that HPV vaccination is helpful in patients already infected with HPV 16 or 18. Vaccination with quadrivalent HPV appears to be safe, and no pregnancy risks are noted.

 

This article shows definitively that vaccination with an HPV quadrivalent vaccine prevents infections and the cervical changes associated with them for those virus subtypes included in the vaccine. The effectiveness is nearly 100% in preventing new HPV 16 or 18 infections, which have been associated in more than 50% of cervical cancers. However, there was only a modest reduction in cervical dysplasia rates, presumably because of other viral subtypes, or perhaps infection with the virus prior to vaccine effect, since most of these women were sexually active prior to and after vaccination. The research that remains to be done is a study looking at younger females, who are not yet sexually active, though such a study would take many years to complete. This study did not show that the vaccine reduces adenocarcinoma of the cervix, which is the primary goal of the vaccine. However, it is well known that high-grade dysplasia of the cervix is a precursor risk factor for adenocarcinoma, and the majority of experts in the field consider this to be an acceptable surrogate endpoint. Thus, it follows that reducing these precursor lesions will prevent adenocarcinoma. At this time, the vaccine appears to be safe and seems to offer at least five years of immunity, based on immunologic testing. It is reasonable, therefore, to recommend the vaccine, though careful studies are needed to guide further implementation in specific populations.

 

 

 

This study in the same journal issue studied the same HPV vaccine, and found similar reductions in CIN 2/3 but no reduction in adenocarcinoma. This study also showed a reduction in non-cervical HPV-related diseases such as warts.

 

 

 

 

 

 

To compare the yield of CT colonography (CTC) to that of colonoscopy in detecting advanced colon neoplasms in a population of patients at average risk for colorectal carcinoma.

 

This is a retrospective study done at one U.S. institution, comparing over 3,000 consecutive screening CTC procedures to over 3,000 consecutive screening colonoscopy procedures. Patients with a history of colon polyps or known bowel disease were excluded. All colonoscopy procedures were done in standard fashion, with sedation, and all polyps regardless of size were removed and sent for analysis. The CTC procedure involved ingestion of a bowel cathartic, along with oral barium tagging and colonic distension with continuous CO2 gas infusion via rectal catheter. CTC patients who had polyps 6-9 mm were offered a choice of either same-day colonoscopy for polypectomy or surveillance with follow-up CTC. Polyps 10mm or larger underwent same-day colonoscopy. Advanced neoplasias were defined as polyps over 10mm, or any polyp with high-grade dysplasia or prominent villous components. Outcomes included the number of advanced adenomas found by either strategy.

 

CT colonography detected similar numbers of advanced neoplasms and cancers compared to optical colonoscopy.

 

 

Most patients (approximately 87% in both groups) had ‘negative’ reports, i.e. no significant findings on the screening procedure (no polyps > 6 mm in size). Less than 10% of patients in the CTC group had a colonoscopy at any time in this study. In the CTC group, 7.7% of patients underwent further imaging to investigate incidentally found extracolonic abnormalities, and in a total of eight (0.3% of patients) extracolonic cancers were found.

 

CONCLUSIONS
CTC compares favorably to colonoscopy at finding asymptomatic colon polyps in a large group of patients at low-risk for colorectal cancer, and reduces the numbers of colonoscopy procedures. However, this study was not a randomized trial; thus there may have been referral bias in patient/physician choice of procedure. Also, this study was done at one institution. The CTC results may not be achievable in other places.

 

Colorectal cancer screening is a proven strategy to reduce colon cancer deaths; however, only about half of eligible patients undergo screening of any kind. CTC represents an alternative to colonoscopy that does not involve sedation and is generally noninvasive. Since the majority of patients who undergo screening have no significant findings, not surprisingly, CTC results in far fewer invasive colonoscopy procedures.

 

While this study suggests that CTC is an effective screening tool for colorectal cancer, the accumulated data are insufficient to say that CTC is equal to colonoscopy. Head to head randomized trials have not been published. Also, CTC has many limitations. It has significant discomfort for the patient (bowel preparation, rectal CO2 insufflation), and is time consuming to do and analyze for the technicians and physicians involved. It may not be cheaper or more readily available than colonoscopy, and CTC often is not covered by third party payors. Finally, it would be difficult to offer same-day colonoscopy in those patients with polyps on CTC, thus requiring another scheduled procedure and bowel preparation for the polypectomy in a substantial minority of screened patients. At this time, it seems reasonable to offer CTC to low-risk patients who may prefer it to invasive colonoscopy, being attentive to insurance coverage and the institutional experience with this relatively new procedure.

 

 

 

 

 

 

To determine the benefits and harms of periodic health evaluations (PHE) in terms of patient outcomes and health care costs.

 

In this study PHE is defined as one or more visits with a health care provider for the primary purpose of assessing patients’ overall health and risk factors for disease that may be prevented by early intervention. The authors developed a model for PHE focused on benefits (e.g. reassurance, improve clinical outcomes) and harms (e.g. loss of time at work, inappropriate tests). This model was used to guide a systematic review of the literature to compare care that incorporated PHE with “usual care”, defined as the delivery of clinical preventive services essentially without scheduled, dedicated check-ups. Appropriate studies were identified, data were extracted and assessed for quality, and synthesized using an accepted evidence-grading scheme to identify and compile the “best available evidence.” Outcomes of PHE were categorized both in terms of direction (beneficial, harmful, mixed, or no effect) and magnitude (small, intermediate, large).

 

After screening thousands of articles, the authors selected 50 that were judged to merit inclusion. These 50 articles reported on 33 studies of which 10 were RCTs and 23 were observational studies. PHE was judged beneficial in yielding improved rates for gyn exam/PAP smear, cholesterol screening, colon cancer screening, and improving patients’ attitudes. Mixed effects were found for counseling, immunizations, mammography, influencing habits, disease detection and control of blood pressure, cholesterol and body mass index. Mixed effects also were found for more long-term economic and clinical outcomes including health costs, disability, hospitalization and mortality. 

 

PHE is associated with improved delivery of some – but not all – recommended clinical preventive services, and with reduction of patient worry. For most short-term and long-term outcomes, the evidence supporting PHE was mixed. No harms were associated with PHE. The heterogeneity of the studies precluded identification of any mechanism by which PHE improves care, but at a minimum, PHE (as opposed to usual care) appears to focus providers on delivery of preventive services, and it allays patients’ worries. 

 

Long the standard of care, PHE has not fared well in the era of evidence-based medicine and practice guidelines. In 1979 the Canadian Task Force on Periodic Health Examination found little evidence in support of PHE. Since then, the American College of Physicians, the American Medical Association, the U.S. Preventive Services Task Force and the U.S. Public Health Service recommended abandoning PHE in favor of preventive services delivered more selectively and in the context of care for other problems. Despite this, most primary care physicians – and the public – believe strongly in the value of PHE, not only to develop the physician-patient relationship, which clearly it does, but also to detect subclinical illness and improve health. Are all these primary care providers and patients deluding themselves? This study suggests no, they are not. While more evidence is needed, particularly on long-term clinical outcomes, the data assembled in this systematic review support PHEs. Hopefully, so too will third party payors.