journalClub

I just got around to looking at the vitamin E study that was publicized at the AHA meetings two weeks ago and published online at the Annals website (to be published in print in January).

It is a meta-analysis of randomized trials of vitamin E, that looks at overall mortality. Trials were analyzed by vitamin E dosage. There were 8 low-dose trials where the vitamin E dose was less than 400 IU daily, with a total of 95,000 subjects; there was no effect on mortality. Pooling the results of the 11 trials (about 41,000 subjects) where the dose was 400 IU or greater, there was an increase in mortality in the vitamin E group. The actual calculated number was 63 deaths per 10,000 persons.

My take on this:

The actual derived number is not meaningful, since results are pooled across a heterogeneous group of subjects, methods and doses. The number 63 per 10,000 should not be taken as is, especially since the confidence interval is 6-119!

On the other hand, the graphic representation of the 19 trials is highly instructive (a picture really is worth a lot of words). Even if one doesn’t place any stock in the pooling of results, just looking at the graphic summary of the trials is very convincing. I believe this is the biggest value of metanalyses: providing a graphic summary of multiple studies.

Since the inflection point for increased risk seems to be around 400 IU daily, and since that is a rather common vitamin E dose, it’s not clear exactly what to think about that dose. But I do feel fairly comfortable telling people who ask about 400 IU of vitamin E or more that I wouldn’t recommend it for prevention and would consider stopping it if they are taking this dose.

In the November 3 Lancet is a meta-analysis entitled “Atenolol for hypertension: is it a wise choice?“.

When compared to placebo for the treatment of hypertension (4 trials with about 3,000 patients total), there was no benefit for atenolol in terms of mortality, cardiovascular mortality or MI. There was a benefit for stroke, but this was mainly from one trial in which atenolol was not used as monotherapy in most patients.

In 3 trials with about 7,000 patients that compared atenolol to other anti-hypertensives, atenolol fared worse than the other medications for all parameters except for MI, where it was about the same.

The authors speculate that the non-lipophilic nature of atenolol (unlike metoprolol and others) might play a role, as might a lesser or absent influence on LVH, compared with other medications. They note that there have been no good trials comparing different beta-blockers in hypertension, thus this need not apply to other beta-blockers. And, of course, beta-blockers have an important role to play in the setting of ischemic heart disease, CHF and arrhythmias.

I’m not a big fan of meta-analyses, in general, but this one is intriguing, and does make atenolol seem much less attractive for hypertension (and perhaps for other indications as well).

In the continuing effort to demonstrate carvedilol’s superiority over metoprolol, comes a study in this week’s JAMA looking at metabolic side-effects of these two beta-blockers in diabetic hypertensives.

Patients with diabetes and hypertension, but without major cardiac disease, who were receiving ACE inhibitors or ARB’s, were first taken off their other anti-hypertensives (if any), but continued on the ACEI or ARB. They were then randomized to carvedilol or metoprolol tartrate, at increasing doses, until either blood pressure was adequately controlled or the maximum dose was attained. At that point, if BP was still not controlled, HCTZ and/or a calcium channel blocker was added to obtain satisfactory BP levels. The primary endpoint was change in HgbA1c levels; insulin levels and lipid levels were also looked at.

In both groups, adequate blood pressure control was achieved, with the same percentage of patients in each group requiring the addition of HCTZ (44%) and a calcium blocker (25%). The mean doses of study medications that were required were carvedilol 17.5 mg bid and metoprolol 128 mg bid. Approximately half the patients in each group required the maximum dose of the study medication: carvedilol 25 mg bid and metoprolol 200 mg bid.

Patients in the carvedilol group had better metabolic results overall. HgbA1c in the carvedilol group increased insignificantly from 7.21 to 7.23; in the metoprolol group it increased significantly by 0.15 from 7.19 to 7. 34 (a 2% change). The urinary albumin/creatinine ratio decreased by 14% in the carvedilol group but increased by 2.5% in the metoprolol group. Lipid changes were slightly in favor of carvedilol, as was insulin sensitivity.

The dose of metoprolol tartrate used in this study was very high. The target dose before adding another anti-hypertensive agent was 200 mg twice daily. Not surprisingly, there was more bradycardia in the metoprolol group. The same percentage of patients in each group required “rescue” antihypertensive treatment. Therefore, the chosen maximum doses of the drugs probably represent an approximately equal antihypertensive effect. Since carvedilol has both alpha and beta adrenergic blocking activity, whereas metoprolol is only a beta-blocker, it is not a complete surprise that a high dose of metoprolol was required to equal the antihypertensive effect of carvedilol. But in the real world, I doubt very much that practitioners would push metoprolol to such a limit, rather than adding a different medication. Which makes one wonder whether the metabolic advantage of carvedilol would have been as great if a more normal metoprolol dose had been chosen.

I was unable to find out the exact rationale behind the dose choices that were made. In the article, the authors state that “A detailed description of the study design and statistical methods has been published elsewhere”. But the reference, #17, indicates an article in press, which is not yet available.

It is interesting to note that in the COMET trial, comparing the beneficial effects of carvedilol to metoprolol in patients with CHF, the target dose of carvedilol was 25 mg bid, that of metoprolol was 50 mg bid. So, when looking at beneficial effects of these drugs, the investigators chose a rather low dose of the “competitor”, when looking at side-effects, they chose a mega-dose.

In the November 11 New York Times, Gina Kolata, referring to the CAMELOT study (just published in JAMA), states:

Although strictly speaking correct, the above sentence is misleading, since it refers to a composite endpoint. Both cardiovascular deaths and overall deaths were insignificantly increased in the treatment arms compared to placebo. Anyone reading Kolata’s sentence would be forgiven for incorrectly concluding that deaths were also reduced. This is a typical example of the difficulty of accurately presenting study results in a bite-sized fashion for the general public.

As for the study itself, I’m not quite sure what it really does demonstrate.

Patients with angiographically documented coronary disease and a mean BP of 129/78 were randomized to daily amlodipine, enalapril or placebo. After two years, the composite endpoint noted above occurred in 23.1% of placebo patients, 20.2% of enalapril patients and 16.6% of amlodipine patients (significant for amlodipine vs placebo; trend not significant for enalapril vs placebo).

In their conclusion, the authors state that:

Blood pressure reduction was about 5/3 mmHg in both treatment groups vs placebo. If the main effect is via BP reduction, and BP was similarly reduced in both treatment groups, why was amlodipine more efficacious? The authors note that once daily enalapril taken in the morning may achieve an identical BP reduction later in the day, but drop off during the night. Perhaps, but just speculation. Much of the benefit of amlodipine was in reducing hospitalizations for angina. When a post-hoc analysis of mortality, MI and stroke was looked at, there was an identical but non-significant trend towards benefit in both treatment groups.

Interestingly, this study was published the same week as the PEACE trial, which appeared in the NEJM. That study looked at an ACE inhibitor, trandolapril, in patients with stable coronary disease and well controlled risk-factors. There was no benefit to the addition of the ACE inhibitor. In this study, blood pressure reduction was only about 3/1.5 mmHg compared with placebo.

Bottom line? Dropping blood pressure lower than what is currently considered normal in patients with CAD is probably good, although not dramatically so. Not a big surprise. Amlodipine reduces hospitalizations for angina. ACE inhibitors may not be the magic bullet the HOPE trial had suggested, if all other risk factors are very well controlled, or perhaps it depends on the specific ACE inhibitor used. Not clear.

I’m not sure how much useful information was added by these two studies.