Angiotensin Blocker Preserves Endothelial Function Better Than Calcium Antagonist

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The angiotensin-receptor blocker (ARB) telmisartan ameliorates endothelial dysfunction following drug-eluting stent (DES) implantation better than the calcium-channel blocker amlodipine in hypertensive patients. Results from a small, randomized trial appear in the February 2012 issue of JACC: Cardiovascular Interventions.

Researchers led by Mitsuyasu Terashima, MD, of Toyohashi Heart Center (Toyohashi, Japan), randomized 42 hypertensive patients with stable angina and single de novo coronary lesions to telmisartan (78.1 mg/day) or amlodipine (7.9 mg/day) following sirolimus-eluting stent (SES; Cypher, Cordis, Miami Lakes, FL) implantation. Since DES implantation impairs local endothelial function, potentially influencing future cardiovascular events, the researchers wanted to evaluate the protective effects of telmisartan, which has unique characteristics compared with amlodipine.

Blood pressure measurements over the 3-month study period were equivalent between groups, showing significant improvement with both agents. Interestingly, LDL cholesterol dropped by 11 ± 21 mg/dL in the telmisartan group, while there was an increase of 7 ± 22 mg/dL in the amlodipine group (P = 0.01). Adiponectin levels, meanwhile, fell in the amlodipine group by 1.6 ± 2.4 mg/dL, while increasing by 0.4 ± 1.0 mg/dL in the telmisartan group (P = 0.02).

ARB Lessens Vasoconstriction

Prior to SES implantation, there was no difference between the 2 groups in mean lumen diameter in response to intracoronary infusion of saline (control), acetylcholine (10^-7 or 10^-6 mol/L), or nitroglycerin. However, 3 months after SES implantation, mean lumen diameters in response to both acetylcholine infusions were larger with telmisartan compared with amlodipine, while nitroglycerin infusion yielded no differences (table 1).

Table 1. Mean Lumen Diameters in Response to Intracoronary Infusion at 3 Months

Prior to SES implantation, there was mild vasoconstriction in both groups in response to acetylcholine, but there was no significant difference in vasoconstriction between the groups until 3 months after stent implantation, at which point it was greater in the amlodipine group (P < 0.0001). Factoring in LDL reductions did not alter these results.

At 3 months, the extent of vasoconstriction in the amlodipine group was greater than prior to stent implantation in response to both acetylcholine 10^-7 mol/L and 10^-6 mol/L (-16.0% vs. -1.8%; P = 0.005; and -35.5% vs. -5.7%; P < 0.0001, respectively). In the telmisartan group, this was true only after infusion of acetylcholine 10^-6 mol/L (-8.7% vs. -6.3%; P = 0.048).

The response to nitroglycerin did not differ between groups before or at 3 months after DES implantation.

“Telmisartan, compared with amlodipine, significantly ameliorated endothelial dysfunction after DES implantation in terms of vasoconstriction induced by acetylcholine,” the researchers conclude. “Although the exact mechanisms of endothelial dysfunction after DES implantation remain unknown, reversal of endothelial dysfunction might improve the long-term outcome in patients treated with DES.”

Multiple Mechanistic Actions Implicated

Dr. Terashima and colleagues note that coronary vasospasm after DES implantation due to endothelial dysfunction has become a concern, potentially leading to serious cardiac events such as MI, fatal arrhythmia, or sudden death. In addition to inhibiting the renin-angiotensin system, telmisartan also exhibits unique peroxisome proliferator-activated-receptor-gamma-mediated effects, which may further improve endothelial dysfunction. This additional vascular protection may be evidenced in the study by the ARB’s LDL-cholesterol-lowering effects.

In a telephone interview with TCTMD, Abhiram Prasad, MD, of the Mayo Clinic (Rochester, MN), noted that his own group’s work supports the mechanistic underpinnings of the study. “Angiotensin is believed to mediate oxidative stress in blood vessels, which is thought to be one of the upstream mediators of why endothelial dysfunction occurs, so blocking that, in theory, is the idea,” he said. “We did some work in the past to show that this group of drugs improves the amount of nitric oxide in the blood vessel, and that might be why blood vessel function improves.”

Dr. Prasad pointed to several previous papers supporting the ability of ACE inhibitors and ARBs to preferentially preserve endothelial function compared with other drug classes, but in patients with atherosclerosis and heart failure, not a PCI population.

“As far as I know, this study is the first that’s shown you can do some intervention in terms of drug therapy and limit the amount of endothelial dysfunction distal to a sirolimus stent,” he said. “It makes sense, based on prior literature. . . . In patients where there may be symptoms related to some amount of endothelial dysfunction after a stent implantation, these drugs may be a potential way of treating it.”

‘Small Group of Patients’ May Benefit

Dr. Prasad noted that the ability of telmisartan to ameliorate stent-related endothelial dysfunction should apply to hypertensive and non-hypertensive patients alike. However, to what extent endothelial dysfunction contributes to disease progression or symptoms following stent implantation is not clear, though the existence of such dysfunction after DES implantation is well documented, he added.

“There are clear case examples in the published literature and in our personal experience where people have developed severe spasm after implantation of a DES, but these are not common. Mild endothelial dysfunction is probably quite common, but not symptomatic,” Dr. Prasad said. “For the occasional patient we all see where they do get terrible spasm, now there’s an evidence base for perhaps using these drugs. The bottom line is this is important from a pathophysiological standpoint; and from a clinical standpoint, it’s probably important for a small group of patients who have severe endothelial dysfunction.”

An important caveat, he added, is that only SES were used in the study as opposed to the different device types currently used in practice. Nevertheless, a large population currently has SES implanted, and many DES used in clinical practice contain drugs similar to sirolimus. “I would think the same phenomenon [of endothelial function] would be seen,” Dr. Prasad said. “It may be a question of magnitude with the newer stents. There may be less severe dysfunction, but it’s likely there is some that occurs.”

 

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Source:
Terashima M, Kaneda H, Nasu K, et al. Protective effect of telmisartan against endothelial dysfunction after coronary drug-eluting stent implantation in hypertensive patients. J Am Coll Cardiol Intv. 2012;5:182-190.

 

Disclosures:

• The study was supported by a grant from the Japan Vascular Disease Research Foundation.
• Drs. Terashima and Prasad report no relevant conflicts of interest.

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