In the JournalsPerspective

Review: No reason to use ACE inhibitors for hypertension

Franz Messerli
Franz H. Messerli

In a review published in the Journal of the American College of Cardiology, four experts stated there is no reason to use ACE inhibitors to treat hypertension when angiotensin receptor blockers can be used instead.

“Because efficacy is similar but adverse events are fewer with [angiotensin receptor blockers], risk-to-benefit analysis in aggregate indicates that at present there is little, if any, clinical reason to use ACE inhibitors for the treatment of hypertension and so-called compelling indications,” Cardiology Today Editorial Board Member Franz H. Messerli, MD, from the department of cardiology and clinical research, University Hospital, Bern, Switzerland, and the division of cardiology, Mount Sinai Medical Center, Icahn School of Medicine, and colleagues wrote.

The researchers reviewed the literature to compare the safety and efficacy of ACE inhibitors and angiotensin receptor blockers for the treatment of hypertension and hypertension associated with compelling indications, including CAD, HF, chronic kidney disease (CKD), diabetes and cerebrovascular disease.

“This topic has been debated ever since ARBs have been on the market,” Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI, associate professor of medicine, director of research of the cardiac catheterization laboratory and director of the Cardiovascular Outcomes Group in the Cardiovascular Clinical Research Center at NYU Langone Health, an author of the review, told Cardiology Today. “Whether to choose ACE inhibitors or ARBs is especially valid question to ask now, as there are many generic ARBs similar to the generic ACE inhibitors.”

Sripal Bangalore, MD, MHA
Sripal Bangalore

Efficacy similar

For BP reduction, “no clinically meaningful difference in antihypertensive efficacy” has been demonstrated between the two drug classes, and “meta-analyses of clinical trials suggest numerically greater reductions in office systolic and diastolic BP with [angiotensin receptor blockers] when compared with ACE inhibitors,” Messerli and colleagues wrote.

Clinical trials have not demonstrated any difference in efficacy between the two drug classes for reducing CV outcomes in patients with hypertension or at high risk for CV events, according to the authors.

Among patients with CAD, angiotensin receptor blockers “reduce CV events, including the risk of MI, as effectively but more safely than ACE inhibitors,” Messerli and colleagues wrote.

Among patients with HF, both drug classes have been shown to be more effective than placebo, and a significant all-cause mortality benefit has been seen with ACE inhibitors but not angiotensin receptor blockers, but the sample size for angiotensin receptor blockers is much smaller, the authors wrote.

Most studies of the drugs in patients with CKD have shown no difference in benefit, but one study of more than 14,000 patients with CKD found that mortality rates were higher in those using ACE inhibitors than in those using angiotensin receptor blockers, according to the researchers.

Most studies of the drugs in patients with diabetes have shown no difference in benefit, but one found angiotensin receptor blockers were better at reducing events than ACE inhibitors regardless of diabetes history, Messerli and colleagues wrote.

The drugs have shown no difference in stroke rates in patients with cerebrovascular disease, according to the researchers.

Adverse event risks

However, the authors wrote, ACE inhibitors have a worse adverse effect profile than angiotensin receptor blockers. A dry, irritating cough is the most common adverse effect of ACE inhibitors and particularly pronounced in Asian patients, they wrote. Angioedema, a more serious adverse effect that is sometimes fatal, is more common in those using ACE inhibitors than in those using angiotensin receptor blockers. Although angioedema is rare, “use of ACE inhibitors could result in several hundred fatalities per year,” Messerli and colleagues wrote.

In addition, withdrawal rates resulting from adverse events are higher with ACE inhibitors than with angiotensin receptor blockers, Messerli and colleagues wrote.

“The present data are prone to swiftly archive [ACE inhibitors] into the list of drugs of historical interest only,” the authors wrote in a press release.

“The general perception has been that ACE inhibitors are better than ARBs,” Bangalore, a member of the Cardiology Today Editorial Board, said in an interview. “That appears to be an aftereffect of HF trials showing that ACE inhibitors were beneficial. In clinical practice, an ACE-first approach is generally used, regardless of what condition is being treated. These findings should at least lead to more of an evidence-based discussion about whether to use ACE inhibitors or ARBs. This is important because the side effects from ACE inhibitors are more prominent in certain subgroups. For example, Asians have a high incidence of ACE inhibitor-induced cough. If the message that ACE inhibitors should be used first is propagated, many patients may become noncompliant. Now is a good time to debate if that approach is valid.” – by Erik Swain

For more information:

Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI, can be reached at sripalbangalore@gmail.com.

Disclosures: Messerli reports he has served as a consultant or adviser for Abbott Vascular, Daiichi Sankyo, Hikma, Ipca, Menarini, Medtronic, Pfizer, Relypsa, Sandoz, Servier and WebMD. Bangalore reports he has received grants from Abbott Vascular and the NHLBI; has been on the advisory boards of Abbott Vascular, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Menarini, Pfizer and The Medicines Company; has been a consultant for Abbott Vascular and Merck; and has served as a consultant or advisor for Gilead. Please see the review for all other authors’ relevant financial disclosures.

Franz Messerli
Franz H. Messerli

In a review published in the Journal of the American College of Cardiology, four experts stated there is no reason to use ACE inhibitors to treat hypertension when angiotensin receptor blockers can be used instead.

“Because efficacy is similar but adverse events are fewer with [angiotensin receptor blockers], risk-to-benefit analysis in aggregate indicates that at present there is little, if any, clinical reason to use ACE inhibitors for the treatment of hypertension and so-called compelling indications,” Cardiology Today Editorial Board Member Franz H. Messerli, MD, from the department of cardiology and clinical research, University Hospital, Bern, Switzerland, and the division of cardiology, Mount Sinai Medical Center, Icahn School of Medicine, and colleagues wrote.

The researchers reviewed the literature to compare the safety and efficacy of ACE inhibitors and angiotensin receptor blockers for the treatment of hypertension and hypertension associated with compelling indications, including CAD, HF, chronic kidney disease (CKD), diabetes and cerebrovascular disease.

“This topic has been debated ever since ARBs have been on the market,” Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI, associate professor of medicine, director of research of the cardiac catheterization laboratory and director of the Cardiovascular Outcomes Group in the Cardiovascular Clinical Research Center at NYU Langone Health, an author of the review, told Cardiology Today. “Whether to choose ACE inhibitors or ARBs is especially valid question to ask now, as there are many generic ARBs similar to the generic ACE inhibitors.”

Sripal Bangalore, MD, MHA
Sripal Bangalore

Efficacy similar

For BP reduction, “no clinically meaningful difference in antihypertensive efficacy” has been demonstrated between the two drug classes, and “meta-analyses of clinical trials suggest numerically greater reductions in office systolic and diastolic BP with [angiotensin receptor blockers] when compared with ACE inhibitors,” Messerli and colleagues wrote.

Clinical trials have not demonstrated any difference in efficacy between the two drug classes for reducing CV outcomes in patients with hypertension or at high risk for CV events, according to the authors.

Among patients with CAD, angiotensin receptor blockers “reduce CV events, including the risk of MI, as effectively but more safely than ACE inhibitors,” Messerli and colleagues wrote.

Among patients with HF, both drug classes have been shown to be more effective than placebo, and a significant all-cause mortality benefit has been seen with ACE inhibitors but not angiotensin receptor blockers, but the sample size for angiotensin receptor blockers is much smaller, the authors wrote.

Most studies of the drugs in patients with CKD have shown no difference in benefit, but one study of more than 14,000 patients with CKD found that mortality rates were higher in those using ACE inhibitors than in those using angiotensin receptor blockers, according to the researchers.

Most studies of the drugs in patients with diabetes have shown no difference in benefit, but one found angiotensin receptor blockers were better at reducing events than ACE inhibitors regardless of diabetes history, Messerli and colleagues wrote.

The drugs have shown no difference in stroke rates in patients with cerebrovascular disease, according to the researchers.

Adverse event risks

However, the authors wrote, ACE inhibitors have a worse adverse effect profile than angiotensin receptor blockers. A dry, irritating cough is the most common adverse effect of ACE inhibitors and particularly pronounced in Asian patients, they wrote. Angioedema, a more serious adverse effect that is sometimes fatal, is more common in those using ACE inhibitors than in those using angiotensin receptor blockers. Although angioedema is rare, “use of ACE inhibitors could result in several hundred fatalities per year,” Messerli and colleagues wrote.

In addition, withdrawal rates resulting from adverse events are higher with ACE inhibitors than with angiotensin receptor blockers, Messerli and colleagues wrote.

“The present data are prone to swiftly archive [ACE inhibitors] into the list of drugs of historical interest only,” the authors wrote in a press release.

“The general perception has been that ACE inhibitors are better than ARBs,” Bangalore, a member of the Cardiology Today Editorial Board, said in an interview. “That appears to be an aftereffect of HF trials showing that ACE inhibitors were beneficial. In clinical practice, an ACE-first approach is generally used, regardless of what condition is being treated. These findings should at least lead to more of an evidence-based discussion about whether to use ACE inhibitors or ARBs. This is important because the side effects from ACE inhibitors are more prominent in certain subgroups. For example, Asians have a high incidence of ACE inhibitor-induced cough. If the message that ACE inhibitors should be used first is propagated, many patients may become noncompliant. Now is a good time to debate if that approach is valid.” – by Erik Swain

For more information:

Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI, can be reached at sripalbangalore@gmail.com.

Disclosures: Messerli reports he has served as a consultant or adviser for Abbott Vascular, Daiichi Sankyo, Hikma, Ipca, Menarini, Medtronic, Pfizer, Relypsa, Sandoz, Servier and WebMD. Bangalore reports he has received grants from Abbott Vascular and the NHLBI; has been on the advisory boards of Abbott Vascular, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Menarini, Pfizer and The Medicines Company; has been a consultant for Abbott Vascular and Merck; and has served as a consultant or advisor for Gilead. Please see the review for all other authors’ relevant financial disclosures.

    Perspective

    This a very carefully constructed analysis. Dr. Messerli and colleagues are well-established clinicians and investigators. The data which they cite are from randomized trials in which patients are assigned to one of two treatment arms, and then an intention-to-treat analysis is performed. In this context, however, I would think the on-therapy response, as opposed to the intention-to-treat analysis, is the most important, because there are millions of people taking either ACE inhibitors or angiotensin receptor blockers successfully, with well-controlled BP, without adverse experiences, with improved cardiac performance if they have HF and with continued protection in the setting of diabetes. Therefore, it may be premature to put ACE inhibitors on the trash heap, because many patients do extraordinarily well with them.

    My personal experience with ACE inhibitors has been that the incidence of angioedema is quite a bit lower than what is often cited in the literature, but objective trials may have more reliable data. Also, a lot of coughs that get attributed to ACE inhibitors and lead to discontinuation of therapy turn out to be attributable to allergies, bronchitis, etc. Therefore, some withdrawals for cough may be inappropriately attributed to the drug.

    It must also be noted that there is considerable variation in the potency among the drugs in both classes. Many of these trials are done in comparison to enalapril, which is known to have a somewhat high side-effect profile, especially with regard to cough, whereas drugs like fosinopril have a lower side-effect profile and might be better tolerated. Losartan is probably the least effective of the angiotensin receptor blockers, whereas azilsartan is the most, with the others somewhere in between.

    What I take from the literature is that agents that disrupt the renin-angiotensin-aldosterone system are often helpful, effective and well-tolerated in hypertensive and other patient populations. For me, they form the foundation of most patients’ treatment. Picking the individual drug that works for the individual patient is the strategy that serves them best.

    Numerous trials of angiotensin receptor blockers have suggested they have few side effects, and in some cases may even have fewer side effects than placebo, which also suggests that uncontrolled high BP is not as asymptomatic as some might think. I suspect that guidelines documents may make note of these observations, but I would not anticipate them rescinding support for the use of ACE inhibitors, especially for the millions of patients with many underlying indications or comorbidities who have taken them successfully.

    • Randall M. Zusman, MD
    • Director, Division of Hypertension Massachusetts General Hospital Heart Center Associate Professor of Medicine Harvard Medical School

    Disclosures: Zusman reports no relevant financial disclosures.