Two papers in the Archives of Internal Medicine cast doubt on the benefits of statins for primary prevention.
In a meta-analysis, researchers combined data from 11 placebo-controlled trials of statin use in some 65,000 high-risk patients without cardiovascular disease at baseline. During nearly 4 years of treatment, LDL levels were lower in statin than in placebo users (mean, 94 vs. 134 mg/dL) — but there was no difference in all-cause mortality. Editorialists say the analysis "makes it clear that in the short-term, for true primary prevention, the benefit, if any, is very small."
In another paper, investigators took a closer look at the JUPITER trial, in which rosuvastatin reportedly lowered cardiovascular risk by 50% among patients without heart disease or hypercholesterolemia but with high C-reactive protein. The investigators say the trial was "flawed" — it was stopped too early, data on cardiovascular mortality were lacking, and more than half the researchers had financial ties to industry. Accordingly, they conclude: "The results of the trial do not support the use of statin treatment for primary prevention."
Tuesday, June 29, 2010
Wednesday, June 2, 2010
VAL-HEFT and CHARM say yes to ARB/ACEI for CHD
However, it is different from the VAL-HEFT and CHARM studies, which also examined the combination of an ACE inhibitor with an ARB {2,3}. The latter two trials showed an added benefit from the combination therapy, but they examined different patient populations (congestive heart failure) and their design did not stress an increase in the dose of ACE inhibitor to a maximum, which could account for the differences in their results. Questions also remain about the benefits of ACE inhibitor-ARB combination therapy in patients with established chronic kidney disease, given the benefits described in earlier (albeit much smaller) clinical trials and about the role of novel renin-inhibitor aliskiren. References: {1} Anderson et al., Am Heart J 2008, 155:706-711 [PMID:18371480]; {2} Krum et al., Eur J Heart Fail 2004, 6:937-945 [PMID:15556056]; {3} Pfeffer et al., Lancet 2003, 362:759-766 [PMID:13678868]. Trial registration: NCT00153101.
ontarget and valiant says no to ARB/ACEI combo
This study concludes that the angiotensin-receptor blocker (ARB) telmisartan was equivalent to the ACE inhibitor ramipril in preventing cardiovascular events in high-risk patients with vascular disease or diabetes mellitus. The combination of telmisartan and ramipril offered no advantage over maximally dosed ramipril and was associated with higher risk of adverse events. The authors examined the non-inferiority of therapy with telmisartan compared to maximally dosed ramipril and to combination therapy of telmisartan plus ramipril in high-risk patients with established cardiovascular disease or diabetes mellitus with end-organ damage (but normal serum creatinine). The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study was a randomized, controlled, double-blind trial. There was no difference in the three groups in incidence of primary outcome. Patients in the telmisartan group had a lower incidence of cough and angioedema, but a higher incidence of hypotension compared to patients on ramipril. The incidence of syncope was identical in these two groups. Patients in the combination arm had a higher incidence of hypotension, syncope and renal dysfunction compared to patients in the ramipril arm. Another interesting finding was the fact that ACE inhibitor-ARB combination therapy did not result in better outcomes compared to ramipril therapy alone, in spite of better blood pressure (BP) control seen in patients treated with the combination regimen (2.4/1.4mmHg lower BP in the combination arm). One potential explanation for this is the higher incidence of adverse effects such as hypotension and renal complications seen with combination therapy, which might have offset the benefits of better blood pressure reduction. The conclusion here, regarding combination therapy with ACE inhibitors plus ARBs, is similar to the VALIANT trial which examined the combination of full dose captopril plus valsartan
Effect of PPI's on b12, iron, gastrin
The basis for these questions is the fact that levels of all 3 of these substances (hormones, vitamins, and elements) are in some way dependent on or related to gastric acid secretion. As such, any agent that affects gastric acid secretion may affect these specific substances, and because PPIs are potent antisecretory agents, they should in turn affect them to a greater degree.
Gastrin is a potent acid secretagogue that is released from "G" cells in the antrum of the stomach and the duodenum in response to a meal. The feedback inhibition for gastrin is acid present in the lumen of the stomach and small intestine. The use of any agent that inhibits gastric secretion of acid (H2-receptor antagonists or PPIs) will result in a rise in serum gastrin as the feedback inhibition of gastrin release is diminished. Gastrin levels are commonly elevated in patients taking PPIs, but only unusually to a significant degree. No adverse clinical events have been noted with the generally mild hypergastrinemia seen with PPI therapy during the 14 years these compounds have been in clinical use.
Serum B12 levels are in part dependent on the presence of intrinsic factor secreted by parietal cells along with acid and the subsequent binding of intrinsic factor to free cobalamin in the small intestine. PPI use decreases the secretion of acid from parietal cells and of intrinsic factor as well. Studies of B12 levels in patients taking PPIs chronically have demonstrated a clinically insignificant decrease in serum B12 levels, but there have been no reports of B12 deficiency despite 14 years of widespread use of these compounds. If one is concerned about the possibility of B12 deficiency, supplementation of this vitamin can be achieved at little cost. The need for such supplementation has never been demonstrated despite close scrutiny of this physiology over time.
Iron absorption is facilitated in part by the conversion of heme in the presence of acid to a different state. Decreased acid secretion in the presence of PPI therapy theoretically would decrease the presence of this converted iron and could lead to decreased absorption. However, iron malabsorption has never been demonstrated in patients taking PPIs.
Why have there been no clinically adverse events related to these potential physiologic perturbations despite widespread use of PPIs? The answer lies in the extent and duration of the antisecretory therapy with these compounds. In general, most of these agents inhibit acid secretion only for 10-12 hours of the day, meaning that for most of the day, normal acid secretion is taking place and these physiologic events are proceeding as expected. If an agent becomes available that truly results in achlorhydria (absent acid secretion), then these physiologic consequences may become clinically relevant and worth monitoring. Until that time, there is little likelihood of encountering a patient who develops a clinically relevant abnormality of these physiologic processes due to the fact that he or she is taking a PPI.
Gastrin is a potent acid secretagogue that is released from "G" cells in the antrum of the stomach and the duodenum in response to a meal. The feedback inhibition for gastrin is acid present in the lumen of the stomach and small intestine. The use of any agent that inhibits gastric secretion of acid (H2-receptor antagonists or PPIs) will result in a rise in serum gastrin as the feedback inhibition of gastrin release is diminished. Gastrin levels are commonly elevated in patients taking PPIs, but only unusually to a significant degree. No adverse clinical events have been noted with the generally mild hypergastrinemia seen with PPI therapy during the 14 years these compounds have been in clinical use.
Serum B12 levels are in part dependent on the presence of intrinsic factor secreted by parietal cells along with acid and the subsequent binding of intrinsic factor to free cobalamin in the small intestine. PPI use decreases the secretion of acid from parietal cells and of intrinsic factor as well. Studies of B12 levels in patients taking PPIs chronically have demonstrated a clinically insignificant decrease in serum B12 levels, but there have been no reports of B12 deficiency despite 14 years of widespread use of these compounds. If one is concerned about the possibility of B12 deficiency, supplementation of this vitamin can be achieved at little cost. The need for such supplementation has never been demonstrated despite close scrutiny of this physiology over time.
Iron absorption is facilitated in part by the conversion of heme in the presence of acid to a different state. Decreased acid secretion in the presence of PPI therapy theoretically would decrease the presence of this converted iron and could lead to decreased absorption. However, iron malabsorption has never been demonstrated in patients taking PPIs.
Why have there been no clinically adverse events related to these potential physiologic perturbations despite widespread use of PPIs? The answer lies in the extent and duration of the antisecretory therapy with these compounds. In general, most of these agents inhibit acid secretion only for 10-12 hours of the day, meaning that for most of the day, normal acid secretion is taking place and these physiologic events are proceeding as expected. If an agent becomes available that truly results in achlorhydria (absent acid secretion), then these physiologic consequences may become clinically relevant and worth monitoring. Until that time, there is little likelihood of encountering a patient who develops a clinically relevant abnormality of these physiologic processes due to the fact that he or she is taking a PPI.
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