CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Diabetologist Physician, Director – Diabetes and Heart Research Centre (DHRC), Dhanbad, Chairman – RSSDI Jharkhand, Editor – CME INDIA.
21 Clinical Pearls – You must be aware
Wisdom worth Pondering
1. 2021 follows 3 main options among Anti-hypertensives
2. Unfavourable metabolic effects blasted to disproportionate fear
3. The amount of blood pressure reduction is the key, not the choice of medication?
4. Knowing Diuretics
- Thiazide diuretics inhibit the reabsorption of luminal sodium in the early distal convoluted tubule, initially promoting natriuresis and diuresis.
- However, after a few days, there is re-equilibration of sodium homeostasis by the kidney, and blood-pressure lowering persists through vasodilation in the absence of volume depletion.
- Thiazide diuretics can be differentiated into thiazide-type (hydrochlorothiazide or HCTZ) and thiazide-like (chlorthalidone, indapamide) based on molecular structure, mechanism of action, and efficacy.
- They present a flat dose-response curve with a greater risk of adverse metabolic effects without significant improvement in blood pressure at doses exceeding 2.5 or 25 mg, depending on the diuretic.
5. Efficacy in preventing cardiovascular events
- The inferiority of hydrochlorothiazide (HCTZ) to thiazide-like diuretics and to other antihypertensive classes of medications has been recently reviewed in literature.
- The structure of HCTZ and its site of action differ from thiazide-like diuretics.
- HCTZ has a less than 24-hour duration of action and is less potent than indapamide (INDAP), chlorthalidone (CTDN), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, and calcium channel blockers by 4.2–6.2mm Hg SBP.
- HCTZ was less effective in preventing CVEs compared to enalapril in the ANBP2 trial, to amlodipine in the ACCOMPLISH trial, and to CTDN and HCTZ-amiloride in network analyses of trials.
- HCTZ has been shown to be similar to CTDN in producing gout and hypokalemia.
- In patients with hypertension and diabetes, HCTZ is inferior to INDAP in improving endothelial function and longitudinal strain.
- HCTZ is inferior to SPIR in improving coronary flow reserve.
- The distribution of CTDN into red blood cells creates a reservoir leading to a 2- to 3-day duration of action.
- For reducing CVEs, CTDN was more effective than HCTZ in network analysis.
- In the ALLHAT trial, CTDN was more effective than lisinopril for reducing CVEs and more effective than amlodipine in preventing congestive heart failure.
- While concerns have often been raised regarding CTDN’s tolerability, in the ALLHAT trial, control of BP after 5 years in the CTDN, amlodipine, and lisinopril arms was 68, 66, and 61%, respectively.
- At the 12.5–25mg doses of CTDN, safety concerns stemming from hypokalemia and hyperglycemia appear to be unwarranted.
- Hyponatremia is more common with CTDN than HCTZ but not at equipotent doses, and, perhaps more importantly, the incidence of hyponatremia for both medications is very strongly age related.
- Results from the CLICK trial have disproved conventional wisdom.
- Halving Proteinuria Compared With Controls Is “the Big Finding.”
- Another facet of chlorthalidone’s benefit was that 12 weeks of treatment cut average UACR by 50 percentage points among the 81 chlorthalidone-treated patients compared with the 79 patients randomized to placebo.
- A 50% reduction “is really important” because proteinuria is a major risk factor for progressive CKD.
- Chlorthalidone “is not an agent to prescribe and forget. It’s a very potent drug and you need to monitor patients for complications,” especially patients already on a loop diuretic
- Because chlorthalidone is cheap, easily available, and both the incidence and prevalence of CKD stage 4 are high, the outcomes of this trial will have broad and immediate applicability.
8. So many issues with Clorthalidone too
9. Indapamide – Is it the best thiazide/thiazide-like diuretic?
10. Take home points for HCTZ/CD/IND
- Hydrochlorothiazide has a short duration of action (6-12 hours) compared with chlorthalidone (48-72 hours) or indapamide.
- Indapamide is 10 times as potent as the other 2, with about a 24-hour half-life.
- Chlorthalidone 25 mg/day is more effective in lowering systolic blood pressure than HCTZ 50 mg/day.
- Chlorthalidone leads to significantly fewer cardiovascular events than HCTZ.
- Chlorthalidone and indapamide showed a significant reduction in coronary heart disease, stroke, and cardiovascular events compared with placebo.
- In the setting of better blood-pressure lowering efficacy and favorable cardiovascular outcomes with minimal impact on adverse effects, HCTZ can be substituted by chlorthalidone or indapamide.
11. Potassium-sparing diuretics:
- Potassium-sparing diuretics are more effective in maintaining serum and intracellular levels of potassium.
- Both observational and randomized trial data have highlighted the potential of thiazide and thiazide-like diuretics (generally at higher doses) to cause ventricular ectopy and sudden death and for the addition of potassium-sparing diuretics to avert it.
- SPIR, eplerenone (EPLER), amiloride, and triamterene are all valuable, and the latter 2 drugs have been successfully combined with HCTZ to reduce CVEs relative to placebo.
- In resistant hypertension, both SPIR and amiloride (up to 10mg and with HCTZ) have demonstrated utility overall.
- SPIR has never undergone adequate testing for efficacy in reducing CVEs in unselected hypertensives but does reduce total mortality and sudden death in advanced heart failure.
- In hemodialysis patients, it has been recently shown that SPIR at 25mg, while having no effect on BP, decreased the primary outcome of cardiovascular death and hospitalization for CVEs by 60% (95% CI: 19%–80%), P = 0.017, with fewer numbers of coronary and cerebrovascular events in the SPIR-treated group.
- Nonblood pressure–related benefits of SPIR are further suggested by recent data showing SPIR’s ability to reduce proteinuria by 61% in proteinuric kidney disease, to reduce albuminuria by 60% in type 1 diabetics, to normalize left ventricular hypertrophy in primary aldosteronism and low renin hypertension, and to prevent CTDN-induced sympathetic activation and insulin resistance in hypertensive patients.
- EPLERENONE: In a recent meta-analysis, compared to other antihypertensives, EPLER caused a 1.5mm Hg greater reduction in SBP but similar rates of hyperkalemia.
- EPLER improves endothelial function in patients with hypertension.
- Dose equivalency is approximately 100mg of EPLER to 25mg of SPIR.
- LOOP DIURETICS: As chronic kidney disease transitions from stage 3 to 5, particularly with extracellular fluid volume expansion, loop diuretic therapy becomes the preferred diuretic therapy for management of hypertension.
- Loop diuretics are less effective than thiazide-type drugs in reducing BP in the nonedematous patient as has been shown in a recent Cochrane analysis reporting the SBP/diastolic BP reduction of several loop diuretics in primary hypertension.
- The antihypertensive effect of low-dose loop torasemide is improved with nighttime administration.
12. Choosing a diuretic
- Clinical conditions and preferences discussed in 2017 American and 2018 European Hypertension Guidelines.
- Initial blood-pressure lowering treatment with combinations of 2 agents has been proposed by guidelines and are much effective for achieving blood pressure targets if >20/10 mmHg above the blood pressure goal.
- The decrease in intravascular volume by thiazide diuretics causes reflex activation of the sympathetic nervous system and renin-angiotensin-aldosterone system that counteracts and limits the degree of blood pressure reduction.
- Adding ARBs provides a complimentary blood pressure-lowering effect.
13. What Guidelines say?
- The latest hypertension guidelines have underscored the importance of diuretics for all patients, but particularly for those with salt-sensitive and resistant hypertension.
14. Why ISH changed the policy in 2020?
15. Was not ISH policy change amazing?
- Some guidelines do not group chlorthalidone and indapamide under the heading thiazide-like diuretic, but rather, they treat the two molecules separately.
- In the Latin American Society of Hypertension guidelines, indapamide is preferred in patients with a history of stroke or transient ischemic attack; whereas in the most recent ACC/AHA hypertension recommendations, chlorthalidone is listed as the optimal choice.
- The data that provided the evidence base for the most important ISH recommendation, choice of first and second line treatments for hypertensive patients throughout the world, were derived from trials that enrolled mostly Caucasian patients, few blacks and almost no Hispanics, Asians or others.
16. WHO in 2021 followed ISH
17. Indian Guideline 2019 follows same approach
18. Should Indian guideline look back?
19. Why should Indian guideline modify its stand on thiazide like diuretics?
- A double-blind RCT in Indian patients compared CTD (6.25 mg) with HCTZ (12.5 mg) by 24-h ABPM and found that HCTZ merely converted sustained hypertension into masked hypertension.
- CTD significantly reduced mean 24-h ABP as well as nocturnal BP.
- Like white-coat hypertension, masked hypertension should also be recognized” and that ambulatory blood pressure monitoring (ABPM) is useful to identify these patterns and nocturnal hypertension (nondippers).
- In this regard, differences between chlorthalidone (CTD) and hydrochlorothiazide (HCTZ) are noteworthy, especially the long half-life of CTD (40–60 h vs. 3.2–13.1 h of HCTZ).
- The authors recommend that ACEI+CCB is better than a diuretic-based combination based on the ACCOMPLISH trial. However, in ACCOMPLISH – a sponsored trial, a weaker thiazide-type diuretic HCTZ was used for comparison (and not CTD which has been used in all NIH-funded studies).
- CTD is structurally and pharmacokinetically distinct from HCTZ with a much longer duration of action; and against amlodipine, CTD is the appropriate diuretic to be evaluated, as done by major trials funded by National Institutes of Health.
- The recent American and Canadian hypertension guidelines also have clarified upon the differences between thiazide-type and thiazide-like diuretics with long-acting thiazide-like diuretics like CTD being preferred.
- Indian guidelines too must clearly state this difference while recommending ‘thiazide diuretics’ in management of hypertension.
20. CME INDIA Learning Points
- Diuretics are a popular, heterogenous class of antihypertensives with several decades of clinical application.
- Antihypertensive and beneficial effects can be thwarted in many circumstances, such as by concomitant administration of nonsteroidal anti-inflammatory agents. ACE inhibitors and diuretics NSAIDs including COX-2 inhibitors decrease efficacy of diuretics.
- Dietary factors can also be very important. Excess salt ingestion blocks the antihypertensive effect of diuretics, perhaps by countering volume depletion and reduction in cardiac output, an “acute” phase which may be required for the longer-term, “chronic,” vasodilatory phase associated with diuretic administration.
- In large-scale clinical studies, the ability to reduce CVEs is well documented for CTDN, INDAP, amiloride-HCTZ, triamterene-HCTZ, and, in the context of congestive heart failure and end-stage renal disease, SPIR.
- Selection of the appropriate medication and dose optimizes the administration of diuretics in a variety of circumstances, particularly salt-sensitive hypertension, which is prevalent in the obese, the elderly, and black patients.
- The data support a clear distinction between thiazide and thiazide like diuretics.
- Indapamide and chlorthalidone are sufficiently structurally and mechanistically distinct from HCTZ to warrant a separate classification and clinical data underscore the importance of distinguishing between these molecules in clinical practice.
- In the setting of low renin hypertension, diuretics elevate renin in a dose-dependent manner and, therefore, would be expected to enhance the efficacy of angiotensin-converting enzyme inhibitors and aldosterone receptor blockers.
- Diuretics are critical in the management of resistant hypertension, which affects approximately 5% of all adults and is a major contributor to morbidity and mortality.
- Potassium-sparing diuretics are probably underutilized.
- The number of salt-sensitive patients (i.e., the obese and elderly) is increasing, and the SPRINT trial supports an SBP target of less than 120mm Hg in many patients. Thus, it is likely that diuretics will become even more prominent in the management of hypertension.
- Numerous outcome trials in hypertension have shown the benefit of thiazide or thiazide-type diuretics in preventing cardiovascular disease outcomes, including stroke, heart failure, myocardial infarction, left ventricular hypertrophy and aortic aneurysm, compared to placebo controls.
- Importantly, several common hypertension-related comorbidities, including aging, obesity, diabetes and renal function impairment, are associated with salt sensitivity, which favors diuretic treatment.
- Insufficient diuretic treatment is one of the most frequent reasons for failure to achieve blood pressure targets, and there is increasing evidence that all diuretics are not equal in terms of efficacy and tolerability.
- The increasing use of lower doses of diuretics in combination with ACE inhibitors or ARBs further supports diuretic use, as adverse effects of diuretics are reduced by both dose reduction and by the effects of the accompanying ACE inhibitor or ARB, which counteract the potential adverse effects of diuretics on circulating potassium, calcium, glucose, lipids and uric acid levels.
21. CME INDIA Tail Piece
Based on the Presentation by Dr. N. K. Singh at 16th Asian-Pacific Conference of Hypertension (New Delhi) on 25th November 2021
- Pareek AK, Messerli FH, Chandurkar NB, Dharmadhikari SK, Godbole AV, Kshirsagar PP, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure monitoring. J Am Coll Cardiol. 2016;67:379–89
- Mehta RT, Pareek A, Dharmadhikari S. Compelling therapy of LVH: straight (and not-so-straight) inferences from evidence. Clin Hypertens. 2019;25:25
- Kaplan NM. Chlorthalidone versus hydrochlorothiazide: a tale of tortoises and a hare. Hypertension. 2011;58:994–5
- Journal of Human Hypertension https://doi.org/10.1038/s41371-020-0349-x
- Combination therapy in hypertension: What are the best options according to clinical pharmacology principles and controlled clinical trial evidence? Am J Cardiovasc Drugs. 2015; 15: 185-194
- JAMA Intern Med. 2020;180(4):542–551. doi:10.1001/jamainternmed.2019.7454
- ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981–2997.
- Am J Hypertens, Volume 29, Issue 10, October 2016.
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