Category Archives: gastrointestinal

Why don’t we just put statins in the water supply and be done with it?

Statins and the risk of colorectal cancer in last week’s NEJM is a case-control study from Israel that looked at about 2000 patients with colorectal cancer and a similar number of controls, and found that “the use of statins for at least five years (vs. the nonuse of statins) was associated with a significantly reduced relative risk of colorectal cancer”. The odds ratio was about 0.50.

At the risk of sounding like a broken record, this is yet another case-control study, useful as hypothesis generating, but not much else. The authors performed their analysis adjusting for multiple co-variates, such as aspirin use, vegetable consumption, red-meat consumption, but there is no way they can sufficiently adjust for all variables to convince me.

For one thing, they don’t mention adjusting for low-saturated fat diets which patients who take statins are likely to adhere to. And there are sure to be other confounders associated with statin treatment.

The one fact that almost convinced me was that the authors found no protective effect from non-statin cholesterol lowering agents (fibrates). These are likely to be associated with most of the same confounders as statins. BUT, there were only 20 patients taking these drugs, too few to be statistically reassuring, and the reason for prescribing a fibrate rather than a statin is more likely to be hypertriglyceridemia than hypercholesterolemia, implying a different population and perhaps a different diet as well.

Medpundit is also critical of this study. I have to disagree with her main argument against it, however. She feels that the biggest flaw is that the two groups were not matched for ethnicity, with a higher percentage of Ashkenazi Jews in the cancer group. However, in their adjusted analysis, the authors specifically state that they adjusted for ethnicity. In my opinion, the biggest problem with case-control studies is not that they do not adequately adjust for known confounders, but rather that they don’t take into account confounders they have not thought of.

Aspirin vs. Plavix after upper GI bleeding

What a frustrating paper.

In last week’s NEJM is a study from the Prince of Wales Hospital in Hong Kong looking at clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. More precisely, the authors studied patients who had been on 325 mg aspirin or less, who presented with upper GI bleeding and who were either H. Pylori negative or successfully treated. These patients were then randomized to either 80 mg of aspirin daily plus 20 mg of Nexium (esomeprazole) twice daily, or to 75 mg of Plavix alone. They were then followed for a year.

Recurrent upper-gastrointestinal bleeding occurred in 13 patients on Plavix and in only one patient on aspirin-Nexium. The authors’ last sentence: “Our observations do not support the current recommendation that clopidogrel be used for patients who have major gastrointestinal intolerance of aspirin”. The editorial in the same issue also discusses the question of what to do with patients who have had gastointestinal complications while taking aspirin, and says of the ACC/AHA recommendation to replace aspirin with clopidogrel: “The study by Chan et al. clearly indicates that this recommendation is harmful and that such patients should be given aspirin plus a proton-pump inhibitor.”

Not. At least, not exactly.

Patients who have just had a significant upper GI bleed while taking modest or low dose aspirin are clearly at a high risk for rebleeding, particularly if they are not on long-term acid suppression. So if you randomize these patients to either low-dose aspirin plus a PPI or to Plavix alone, it is not terribly surprising that the Plavix-only patients have a higher incidence of recurrent ulcer bleeding. This is a very unsatisfying comparison. On the one hand a drug, aspirin, that is clearly ulcerogenic and also promotes bleeding taken together with a drug that effectively prevents ulcers (omeprazole). On the other hand, a drug (Plavix) that may be less ulcerogenic but is even more likely to promote bleeding and given without any ulcer prevention. This comparison just muddies the waters. This study does not help distinguish the platelet-antagonizing effect of clopidogrel from any direct effect on the healing of ulcers.

Can anything be learned from this study? Mainly that, in patients with aspirin-induced upper GI bleeding who are H Pylori negative, Plavix should not be given alone as an alternative to aspirin plus a PPI.

It would seem that, in these patients, it is relatively safe to prescribe aspirin plus a PPI. Perhaps Plavix plus a PPI would be even safer, but this is pure speculation; this trial does nothing to address this issue one way or the other. What this means for patients who have gastro-intestinal intolerance of aspirin other than upper GI bleeding is unclear. Patients who have a good reason for being on clopidogrel (such as a recently implanted stent) should not be switched to aspirin plus a PPI alone if they have a GI bleed, at least not on the basis of this study.

Clopidogrel is a very popular and quite expensive drug, and I am annoyed by its overly aggressive promotion by drug reps, but this study doesn’t give me any ammunition in resisting its use.

EUS vs CT for pancreatic cancer

The November 16 Annals has an article from Indiana University comparing endoscopic ultrasound with multidetector CT scanning for the evaluation of suspected pancreatic cancer.

104 patients with suspected non-metastatic pancreatic malignancy underwent both EUS and high-resolution multidetector CT scanning. Of these patients, 41 were managed medically, and 63 underwent surgery. The two modalities were then compared for their accuracy in determining resectability, staging and detection of tumors.

The original hypothesis was that EUS would be better at determining resectability (in particular recognizing unresectable tumors) than CT scanning, and resectability was the study’s primary endpoint. There was no significant difference between the two modalities for this endpoint: resectable tumors were correctly identified by EUS vs CT in 88% vs. 92%. Non-resectable tumors were accurately identified by EUS vs CT in 68% vs 64%. The authors conclude that “if multidetector CT detects a pancreatic mass that seems to be resectable in an appropriate surgical candidate with suspected cancer, preoperative endoscopic ultrasonography does not seem to be necessary unless tissue confirmation of suspected malignancy is desired”.

Secondary endpoints were staging and the actual detection of tumors. In terms of overall staging, endoscopic US was superior to CT scanning, due to better recognition of T3 disease. For nodal staging, there was no significant difference.

Interestingly, EUS was superior to CT scanning in the detection of small tumors. Among the 63 patients who underwent surgery, 53 were found to have cancer. Of these 53, endoscopic ultrasound failed to diagnose 2 tumors less than 25 mm in size; CT scanning missed 10 tumors, 9 of which were less than 25 mm and one greater than 25 mm. Most of these were in the head of the pancreas. The authors do not specifically explain how 10 patients who had no pancreatic masses on CT scanning came to be evaluated for suspected pancreatic cancer, but 4 of them had had biliary stents placed, so presumably biliary obstruction was the presenting symptom for many of these CT-negative cases.

Thus, endoscopic ultrasound was not superior to CT scanning in determining resectability of pancreatic tumors but was superior in picking up small (less than 25 mm) masses that turned out to be cancers at surgery. This study, supported by grants from the American Society of Gastrointestinal Endoscopy, does not make endoscopic ultrasound an obligatory part of the resectability work-up, which was presumably the original intent. It certainly does raise the question of the role of EUS in the work-up of patients with possible pancreatic neoplasms, however, since it was able to pick up small tumors that escaped CT detection.

Another case-control study ?

This week’s JAMA has a cohort study from the Netherlands looking at the risk of community-acquired pneumonia and use of gastric acid–suppressive drugs. The authors used a large, private practice clinical database to investigate a hypothesized linkage between the prescription of proton pump inhibitors or H2 receptor blockers and community acquired pneumonia. In order to adjust for the fact that many patients on these drugs are sicker, or more likely to have certain diseases, the authors performed a nested case-control examination that looked at recent acid-suppression therapy compared with previously discontinued therapy, adjusting for a large number of factors and diseases (such as age, sex, indication for the therapy, presence of diabetes, copd and stomach cancer).

The unadjusted relative risk of pneumonia for patients who had been prescribed acid-suppressant therapy vs. those who had not was quite high (4.5). In the matched, adjusted case-control cohort of recent therapy vs. past therapy, the adjusted odds ratio was 1.63, much lower, but still significant.

I believe it is impossible to properly adjust for all the reasons why pneumonia patients might have been prescribed acid-suppressant therapy shortly before getting pneumonia. Some of the factors that the authors controlled for are surely valid, but there are likely to be others. Even an individual practitioner’s style and personality could be linked with both the likelihood of prescribing these drugs and that particular patient population’s risk for pneumonia. Adequate adjustment is just not possible.

After multiple case-control and cohort studies showed significant cardiovascular benefit from estrogen replacement therapy, properly randomized trials demonstrated that this was not the case, forcing an incredible about-face. One would think that the estrogen replacement scandal would have put a major brake on performing and publishing these sorts of studies, yet they seem be flourishing. Has nothing been learned?