Angiotensin II receptor blocker (ARB) experiences?

#29

Angiotensin Receptor Blockers Do Not Reduce Risk of Myocardial Infarction, Cardiovascular Death, or Total Mortality: Further Evidence for the ARB-MI Paradox

https://www.ahajournals.org/doi/full/10.1161/circulationaha.117.026112

Individual trials of angiotensin II receptor blockers (ARBs) and systematic meta-analyses have repeatedly demonstrated the ARB class to significantly reduce systemic blood pressure, stroke, and the subsequent development of heart failure and diabetes mellitus.1 However, no individual trial or meta-analysis has observed an impact of ARB treatment on the incidence of myocardial infarction (MI), cardiovascular mortality, or all-cause mortality (Table). All-cause mortality is the most comprehensive summary indicator of cardiovascular benefit of treatment2 and, consequently, it is surprising that ARBs have no impact given the other clinical benefits we have just acknowledged.

A systematic review/meta-analysis conducted by Bangalore et al3 demonstrated that in 20 trials of ARB versus placebo (n=66 282) and 21 trials of ARB versus active comparator (n=39 738), ARB in no individual trial improved all-cause mortality. Furthermore, when the trials were analyzed in combination, the impact of ARB on mortality was precisely zero compared with placebo (odds ratio, 1.01; 95% confidence limit, 0.96–1.06) and virtually zero compared with an active comparator (odds ratio, 0.99; 95% confidence limit, 0.95–1.03). Placebo-controlled trials are the most rigorous method of assessing treatment efficacy (as well as harm), and, consequently, it is concerning that other meta-analyses of ARBs versus placebo-controlled trials have also reported a lack of mortality reduction in patients with high risk (Savarese),4 those with diabetes mellitus (Cheng),5 and patients with hypertension (Thomopoulos et al),6 as well as no reduction in MI or cardiovascular mortality (Table).

Thomopoulos et al6 also reported the impact of different drug classes compared with placebo in the treatment of systemic hypertension. Indapamide, calcium channel blockers, and angiotensin-converting enzyme inhibitors (ACEIs) all statistically significantly reduced mortality, whereas 4 other drug classes reduced mortality but not to a degree that was of statistical significance. ARB was the only drug class that failed to reduce death compared with placebo, despite representing the largest group of patients studied (n=65 256) and despite an average blood pressure reduction of 3.7/2.0 mm Hg. Because stroke was reduced by ARBs, cardiovascular and all-cause mortality must have been driven by an excess risk of fatal MI and sudden death. ACEIs but not ARBs reduced coronary heart disease (including nonfatal MI) and cardiovascular death (including fatal MI6), despite both being inhibitors of the renin-angiotensin-aldosterone system.

ACEIs suppress angiotensin II, thereby preventing pathological effects, but they also prevent the breakdown of bradykinin, thereby inducing additional cardioprotective effects. This profile is distinct from the one achieved by use of an ARB that induces selective antagonism of the AT1 angiotensin II receptor, inhibiting a negative feedback loop and consequently increasing angiotensin II levels by 200% to 300%. This may lead to MI as a result of stimulation of the AT2 receptors, which are markedly upregulated and active in atheromatous plaques.1 ACEIs in meta-analyses of placebo-controlled trials conducted in parallel to the ARB meta-analyses discussed above (Thomopoulos et al,6 Savarese,4 Cheng,5 Bangalore et al3) demonstrated a robust 9% to 11% risk reduction in all-cause mortality, 10% to 17% risk reduction in cardiovascular mortality, and 17% to 19% risk reduction in MI (all P<0.05; Table). The divergent effects of ACEI and ARB on both all-cause and cardiovascular mortality are despite their comparator arms having similar risks of both (7.8% versus 9%, 4.7% versus 5.2%, respectively).3

These observations are consistent with an earlier meta-analysis1 that reported that ARBs versus all comparators (11 trials, n=55 050) did not reduce mortality (odds ratio, 1.01; 95% confidence interval, 0.96–1.06, P=0.8) and the risk of MI actually increased 8% (odds ratio, 1.08; 95% confidence interval, 1.01–1.16; P=0.03), with that increase qualitatively apparent in 9 of the trials and statistically significant in 2. This article also included a parallel meta-analysis of ACEI trials. ACEIs versus all comparators (39 trials, n=150 943) reduced the relative risk of total mortality 9% (P<0.0001) and MI by 14% (P<0.0001). The divergent effects in the parallel ACEI and ARB meta-analyses on MI and death were marked, despite their comparator arms having similar cardiovascular risks; rates of global death, MI, and stroke (cerebrovascular accident) were essentially no different (13% versus 14%, 5.8% versus 6.3%, and 4.2% versus 4.4%, respectively). In addition, blood pressure lowering comparable to the risk reduction in stroke, a blood pressure–dependent phenomenon, was also similar.

Divergent cardiovascular effects of ACEIs and ARBs were also confirmed in a meta-regression analysis (n=146 838) by the BPLTTC (Blood Pressure Lowering Treatment Trialists’ Collaboration), as well as being independent of blood pressure lowering.1 For any given blood pressure reduction, ACEIs also reduce the risk of coronary heart disease by an additional 9% (P=0.002), independently of the effects of blood pressure lowering. In contrast, ARBs had no blood pressure–independent effects on coronary heart disease; rather, there was a small, nonsignificant increase in the risk of harm of 7% (–7%: 95% confidence interval, 7 to –24; P=NS), a phenomenon we have called the ARB MI paradox. Specifically, it is paradoxical that no net benefits are observed with ARBs. Furthermore, and most important, for any given blood pressure reduction, ACEIs reduced the risk of MI and death an additional 15% (P=0.002) above that of an ARB.

Head-to-head trials of ARB versus ACEI are of interest, but there is a paucity of data. In the ONTARGET trial (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial),2 the largest ACEI versus ARB controlled trial reported to date (n=17 118), the ARB telmisartan was not statistically equivalent to the ACEI ramipril for a combined cardiovascular end point. The US Food and Drug Administration approved telmisartan as a second-line therapy for those high-risk patients who are ACEI intolerant (New Drug Application 20–850). This decision was influenced by a lack of superiority of telmisartan compared with placebo in the parallel TRANSCEND trial (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease), consistent also with the HOPE-3 trial (Heart Outcomes Prevention Evaluation-3) conducted in patients at intermediate risk (n=12 705; follow-up, 5.6 years)4 in whom candesartan combined with hydrochlorothiazide failed to reduce a combination of cardiovascular events despite a robust reduction in blood pressure of 6.0/3.0 mm Hg.

Angiotensin Receptor Blockers May Increase Risk of Myocardial Infarction

https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.105.594986

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#30

Candesartan failed the ITP.

#31

Interesting with your conclusions here. It is exactly what I’ve concluded. I tell my patients it is best to hit multiple pathways at low-moderate dose, as pushing the dose of any drug yields very little added benefit and often results in side effects.

I generally start with Telmisartan, and don’t push beyond 40 mg, then add Amlodipine 2.5 mg and max at 5 mg, then add indapamide 1.25 mg … The indapamide doesn’t get maximal effects until at least 45 days.

I recently had someone who for 40 years has had uncontrolled hypertension and interestingly it was the indapamide at the end that took them down to a sensible range. I goal for SBP of 115 mmHg - which is naturally a big ask of the drugs when someone is running 180-190 mmHg long term.

In this individual, it wasn’t until week 4 of indapamide that we finally got the movement needed, as much as the first 2 drugs helped a bit.

I prefer this diuretic, as in low dose it rarely affects electrolytes.

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#32

Non peer reviewed commentaries from 2006 and 2017 by the same two authors => ciao :put_litter_in_its_place:

Here’s a more recent peer-reviewed study: Real-World Effectiveness of Beta-Blockers versus Other Antihypertensives in Reducing All-Cause Mortality and Cardiovascular Events 2022

The risk of all-cause mortality was lower for those treated with ACEi, ARB, and CCB, and no difference was observed compared with diuretics (adjusted hazard ratio versus beta-blockers (98.75% CI), for ACEi 0.71 (0.61, 0.83), ARB 0.67 (0.51, 0.88), CCB 0.76 (0.66, 0.88), diuretics 1.06 (0.93, 1.22)).

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So ARBs are the antihypertensive drugs associated with the lowest all-cause mortality. Among ARBs, telmisartan might be the best one according to this study from last year: Long-term mortality and cardiovascular events of seven angiotensin receptor blockers in hypertensive patients: Analysis of a national real-world database: A retrospective cohort study (to conclude this, I used the crude models HR with p-value <0.001 and the high 95% CI of the adjusted models, even though it didn’t reach significance)

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Candesartan is not telmisartan. Telmisartan is superior to candesartan in terms of half life (essential to reduce blood pressure variability, itself more important than mean BP for dementia and long-term lifespan,) insulin sensitivity, and PPARα (among other things):

That’s probably why the ITP is now testing telmisartan.

WOW. Super interesting! After reading a lot of papers it’s exactly the conclusion I reached. We’ve just started telmisartan 20 mg with my doctor (Adam Bataineh). There’s actually a company (George Medicines, which is the for profit arm of the non profit George Institute) developing a single pill combination of telmisartan + amlodipine + indapamide in ultra low (10/1.25/0.625), low (20/2.5/1.25) and standard (40/5/2.5) doses. See their rationale and expected effects here: Optimal Blood Pressure we Should Target? Systolic Under 110 or 100? - #222 by adssx

I contacted them and they expect approval soon :pray:

Are you using indapamide 1.5 mg Slow Release @DrFraser? Or cutting half a pill of indapamide 2.5 mg normal release? (Indapamide 1.25 mg is not available in the UK where I live)

It seems that 1/ indapamide caused less insulin resistance than HCTZ and 2/ indapamide 1.5 mg SR was equivalent in terms of BP lowering to 2.5 mg normal release but with less effect on K (see: Clinical implications of indapamide sustained release 1.5 mg in hypertension - PubMed ). In the UK, indapamide is the recommended and most prescribed thiazide/thiazide-like diuretic.

You said 45 days for indapamide to take effect. What about telmisartan and amlodipine?

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#33

That’s a retrospective cohort study. This meta-analysis included only randomized controlled trials with at least 100 participants and a follow‐up of at least two years. There was no difference in all-cause deaths between ARBs and other antihypertensive drug classes. Myocardial infarction incidence was highest in the ARB group, which supports the ARB-MI paradox.

While ARBs and ACEis are associated with an increased risk of lung cancer. If the drugs reduce CV death but increase cancer incidence, I wouldn’t call them anti-aging drugs.

Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: Meta-regression analysis of randomized trials

Overall, there was a statistically significant relationship between cumulative-exposure to ARBs and risk of cancer; with greater degree of cumulative-exposure resulting in a greater risk ratio for cancer in the ARB arm (slope = 0.07 [95% CI 0.03 to 0.11], z = 3.56, p<0.001 with the fixed effect regression method). In the subgroup of patients where there was universal background ACE-inhibitor use in both arms, again there was evidence of a significant relationship between cumulative-exposure to ARBs and risk of cancer; (slope = 0.10 [95% CI 0.03 to 0.18], z = 2.76, p = 0.006 with the fixed effect regression method) (Fig 1, Panel B). Similarly, there was evidence of a significant relationship between cumulative-exposure to ARBs and risk of cancer in patients not receiving ACE-inhibitor treatment in either of the study arms (slope = 0.09 [95% CI 0.03 to 0.16], z = 2.73, p = 0.006 with the fixed effect regression method) (Fig 1, Panel C). Additionally, the relationship between cumulative exposure and risk of cancer with ARBs was statistically significant in both placebo controlled trials (slope = 0.06 [95% CI 0.01 to 0.12], z = 2.27, p = 0.02 with the fixed effect regression method) (Fig 1, Panel D) and in non-placebo controlled trials (slope = 0.09 [95% CI 0.03 to 0.15], z = 2.91, p = 0.004 with the fixed effect regression method) (Fig 1, Panel E).

there was a statistically significant relationship between cumulative-exposure to ARBs and risk of lung cancer; with greater degree of cumulative-exposure resulting in a greater risk ratio for lung cancer (slope 0.16 [95% CI 0.05 to 0.27], z = 2.93, p = 0.003 with the fixed effect regression method). There were trends for a positive relationship between cumulative exposure and risk of lung cancer with ARBs in both placebo controlled trials (slope 0.12 [95% CI -0.02 to 0.28], z = 1.68, p = 0.09 with the fixed effect regression method) (Fig 4, Panel B) and in non-placebo controlled trials (slope 0.17 [95% CI -0.009 to 0.36], z = 1.86, p = 0.06 with the fixed effect regression method) (Fig 4, Panel C).

Use of ACE (Angiotensin-Converting Enzyme) Inhibitors and Risk of Lung Cancer

https://www.ahajournals.org/doi/10.1161/CIRCOUTCOMES.120.006687

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#34

Already answered on this low-quality paper:

  1. Optimal Blood Pressure we Should Target? Systolic Under 110 or 100? - #257 by adssx
  2. Optimal Blood Pressure we Should Target? Systolic Under 110 or 100? - #258 by adssx
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Rilmenidine vs Telmisartan or other BP meds for Longevity
#35

“Use of high cumulative ACEI doses was associated with modestly increased odds of lung cancer although use of lower doses showed neutral associations. The established benefits of ACEIs should be considered when interpreting these findings.”

This is about ACEIs. Not about ARBs like telmisartan. How is this related to the current discussion?

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#36
  1. Retrospective studies well done can emulate trials.
  2. This Cochrane review does not say that “There was no difference in all-cause deaths between ARBs and other antihypertensive drug classes.” it says:

There was no difference in deaths from all causes between CCBs and other blood pressure‐lowering medications. Diuretics probably reduce total cardiovascular events and congestive heart failure more than CCBs. CCBs probably reduce total cardiovascular events more than beta‐blockers. CCBs reduced stroke when compared to angiotensin‐converting enzyme (ACE) inhibitors and reduced heart attack when compared to angiotensin receptor blockers (ARBs), but increased congestive heart failure when compared to ACE inhibitors and ARBs.

It adds:

Many of the differences found in the current review are not robust, and further trials might change the conclusions.

In any case, they looked at all ARBs and not specifically telmisartan. For telmisartan and risk of MI, I could only find this paper: Impact of telmisartan on cardiovascular outcome in hypertensive patients at high risk a Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease subanalysis 2014

Moreover, data from this post-hoc analysis suggest that MI may be less frequent in hypertensive patients treated with telmisartan (3.8 vs. 5.1%; P < 0.05).

Of course, the recommended practice in all national guidelines for blood pressure reduction is to combine drugs to get the best of both worlds.

So, if people have elevated BP, ARBs look like the best option. Especially given that their side effects are equivalent to placebo. See this massive cohort study of 3 million patients: "In our large-scale, observational network study, ARBs do not differ statistically significantly in effectiveness at the class level compared with ACE inhibitors as first-line treatment for hypertension but present a better safety profile. These findings support preferentially prescribing ARBs over ACE inhibitors when initiating treatment for hypertension." (Comparative First-Line Effectiveness and Safety of ACE (Angiotensin-Converting Enzyme) Inhibitors and Angiotensin Receptor Blockers: A Multinational Cohort Study 2021 => ARB on the beneficial side of null vs ACEI for acute MI btw). Among ARBs, for all the reasons already given, low-dose telmisartan (20 mg) looks like the best bet.

Does it mean that telmisartan is an “anti-aging drug” and that everyone, including people with SBP already below 115 mm Hg should take it? No. But for people with elevated BP, it’s a no brainer.

#37

I am currently taking telmisartan but I think I will switch to ramipril. My main objective is to reduce stroke risk as my brother had one.

Many people take blood pressure medications to reduce the risk of ischemic or hemorrhagic stroke.
Overall, ARBs seem less effective for stroke prevention than ACE inhibitors.

“The HOPE trial found that ramipril significantly reduced stroke risk by 32% compared to placebo in high-risk cardiovascular patients. This included reductions in both ischemic and hemorrhagic stroke”

The study suggests that even a modest decrease in blood pressure reduces stroke risk,
though, oddly, ARBs don’t seem to.
“The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44”)

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#38

You’re citing papers from 2002…

As said above, ARBs might be a bit better for stroke vs ACEIs according to this massive cohort study (non statistically significant though): Comparative First-Line Effectiveness and Safety of ACE (Angiotensin-Converting Enzyme) Inhibitors and Angiotensin Receptor Blockers: A Multinational Cohort Study 2021

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The best comparison of telmisartan vs ramipril is the large (n=25,620) ONTARGET trial: Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events 2008

The main secondary outcome was a composite of death from cardiovascular causes, myocardial infarction, or stroke, which was the primary outcome in the Heart Outcomes Prevention Evaluation (HOPE) trial.
The secondary outcome — death from cardiovascular causes, myocardial infarction, or stroke — occurred in 1210 patients (14.1%) in the ramipril group and in 1190 patients (13.9%) in the telmisartan group (relative risk, 0.99; 95% confidence interval [CI], 0.91 to 1.07; P=0.001 for noninferiority).

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See also: Preventing stroke: the PRoFESS, ONTARGET, and TRANSCEND trial programs 2009

In a combined analysis of PRoFESS and TRANSCEND, the incidence of the composite of stroke, myocardial infarction, or vascular death was 12.8% for telmisartan versus 13.8% for placebo (hazard ratio 0.91; 95% CI 0.85–0.98; P = 0.013).

And: Superior stroke prevention with angiotensin receptor blockers compared with other antihypertensive drugs 2023

Among the drugs used, angiotensin receptor blockers provided superior stroke prevention compared to angiotensin converting enzyme inhibitors and other antihypertensive drugs.

So there’s zero reason to switch from telmisartan to ramipril.

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#39

So, the 2002 study was a good study and is likely to be as valid as the newer study. Newer does not necessarily mean better.
Also from the study you cite: “Across secondary and safety outcomes, patients on ARBs had significantly lower risk of angioedema, cough, pancreatitis, and GI bleeding.”

From the study I cite:
“The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44”)

You are in denial about this?

#40

The 2002 study was good. The more recent ones I mentioned are better. (And not funded by the drug manufacturer… But I’ll put this aside.)

The more recent studies I shared showed that ramipril (resp. other ACEIs) was not superior (and even potentially a bit inferior) to telmisartan (resp. other ARBs) in terms of stroke (and other end points) in hypertensive people. That’s it. There’s 0 studies or papers suggesting otherwise. If you find a paper comparing telmisartan to ramipril and finding a higher rate of stroke in telmisartan, let me know!

(also in the 2002 study, “Participants were aged 55 or over and were at high risk of cardiovascular events because of previous coronary artery disease, cerebrovascular disease, or peripheral arterial disease or diabetes plus one additional risk factor.” I don’t know if these are the traditional inclusion criteria for antihypertensive drug trials as I cannot find in the paper the list of these “additional risk factors”.)

Yes, that’s why telmisartan is better than ramipril. (do you know that telmisartan is an ARB?!)

Yes, it’s amazing. And the ONTARGET trial comparing telmisartan to ramipril found that telmisartan was doing as good if not better.

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#41

Okay, okay! I won’t switch from telmisartan. :sweat_smile:

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#42

Haha it’s okay. I just didn’t want people reading us to believe that ACEI/ramipril was significantly better than ARB/telmisartan for stroke prevention as current evidence doesn’t show this. Of course, future studies might change the conclusion. But as of today, the best first line anti hypertensive seems to be a combination [telmisartan + (amlodipine and/or indapamide)].

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#43

Just to be clear, is there an intrinsic reason why telmisartan + amlodipine and/or indapamide are superior to higher-dose telmisartan, or is it simply the aversion of possible side effects that come from higher-dose telmisartan? In other words, if a patient is effectively controlling hypertension with 80 mg telmisartan without side effects, is it nonetheless beneficial to switch to lower-dose telmisartan + amlodipine and/or indapamide?

#44

I mentioned the two-drug combination for therapy initiation only. Here’s the rationale: Optimal Blood Pressure we Should Target? Systolic Under 110 or 100? - #244 by adssx

If someone is already on telmisartan 80 mg monotherapy and well-controlled: If it ain’t broke, don’t fix it? :man_shrugging:

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#45

Preprint but great team: Association between Class of Antihypertensive Drugs and Risk of Incident Dementia: A Multinational Population-Based Cohort Study 2024

1,982,839 individuals followed over more than 6 years in 4 countries (UK, HK, Sweden, and Australia):

Our study supports the use of ARBs compared to ACEI when considering the risk of cognitive decline and dementia, based on a multi-ethnic cohort with a long median follow-up time.

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Unfortunately, they didn’t do the job properly and didn’t distinguish DHP CCBs (e.g., amlodipine, associated in many studies with lower rate of dementia) from non-DHP CCBs and thiazide/thiazide-like diuretics (e.g., indapamide) from other diuretics (e.g., loop diuretics).

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#46

What is the lowest effective dose of Telmisartan? I saw you guys mentioned 20 mg, but my pharmacy only gives 40 mg. Is 20 mg still highly effective? @adssx @desertshores

#47

I broke 40 milligrams of telmisartan into two parts, so half a tablet is 20 milligrams per day

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#48

Thank you. I just did a search and it confirms you can split it in half with no lose of efficacy

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