October 14th, 2013

The Benefits of Switching From Hydrochlorothiazide to Chlorthalidone: What’s Stopping Us?

As a medical student, I’m currently on a nephrology service and hypertension, cardiovascular (CV) events, and diuretics have been on my mind a lot, particularly the issue of chlorthalidone (CTDN). Released at about the same time as hydrochlorothiazide (HCTZ) — 1959 and 1960, respectively — there is great evidence of CTDN’s non-inferiority, and with the exception of a study published a few months ago in the Annals of Internal Medicine that garnered some strong critiques of its validity, CTDN has consistently shown to be superior to HCTZ for the prevention of CV events in every analysis short of a head-to-head randomized, controlled trial. Additionally, the medication benefit cannot entirely be explained by the difference in systolic office blood pressure, which points to some other beneficial mechanisms.

Researchers at St. Vincent’s Medical Center in Bridgeport, CT, have published a nice analysis using data collected on over 50,000 patients from various trials that shows the calculated percentage risk reduction of CV events in patients with congestive heart failure who were prescribed CTDN vs. HCTZ was 23% (95% CI, 2-39; P=0.032), and in all CV events was 21% (95% CI, 12–28; P<0.0001). Relative to HCTZ, the number needed to treat with CTDN to prevent one CV event over five years was 27.

What other medication class could have a drug that is 23% more effective than standard practice with an equivalent side effect profile and the result not be considered a major breakthrough? If there are over 134 million prescriptions of HCTZ (48 million as the sole blood pressure medication), that’s 4.96 million fewer CV events in five years. This benefit could be gained simply by switching from one monetarily equivalent, generic, pharmacologically similar medication to another.

The part that bothers me is that this is something the more academically inclined clinicians are aware of and occasionally write about, lamenting how this is an unfortunate issue. It wasn’t hard to find articles on the data and information I listed above. If our ultimate goals are to be patient advocates and promoters of health, isn’t this something we should be actively trying to change? When I ask doctors about why they don’t prescribe it, I usually get:

1. I haven’t heard of that medication.
2. I didn’t know there was anything better.
3. It is only offered in combination with three other blood pressure meds.
4. It only comes in a dose that’s twice the actual recommended starting amount.

The first two reasons are a failure of dissemination and implementation of ideas, which to me are issues that should be soon resolved now that we live in a connected world that is transitioning care to EMR-based systems. It would be easy to have a clinical decision tool to search every patient on HCTZ and ask if you’d like to switch them to CTDN. To think that the flow of ideas still operates in Balas and Boren’s “17 years, 13% translation” is frustrating, and I think the CDC or the AHA could do more to promote these changes. Is a campaign to prevent almost 5 million CV events in five years unappealing? Can some monetary incentive (reward or punishment) be incorporated as part of the new focus on pay-for-performance?

The second two reasons are flaws in U.S. health policy. The fact that the only way drug regulatory changes occur is when a company stands to benefit monetarily is fully exposed in this setting. If Medicare is one of the major purchasers of these medications, as well as the sufferer of poor outcomes that can occur with CV events, the federal government would benefit monetarily from this change, as well. Is there a reason why it could not act like a commercial entity to apply to the FDA to allow for CTDN to be combined with the same medications as HCTZ? Or that it should be able to be dispensed at 12.5 mg a tablet rather than 25 mg?

Irrespective of the benefit the government would receive, how is it that this profession and organizations like the Patient-Centered Outcomes Research Institute don’t put forth a more concerted effort to tackle such an issue? No new incredible drugs need to be made. No fantastic leaps in science or efficiency. What stands in the way is simply a bureaucratic issue that’s non-ideological, and the overwhelming majority agree that these changes will lead to better health outcomes. What are the actual steps that would be necessary for regulatory approval for combination medications for something that has been reliably used with other hypertension medications for close to half a century?

It frustrates me because of how frequently physicians claim that the problems with healthcare in the U.S. are beyond our control. In recent surveys we place more blame on insurance companies, hospital management, etc., than we do ourselves. But when we have the opportunity to truly be an advocate for something that could have a tangible and meaningful impact far beyond an HCAHPS survey or proton accelerators for prostate therapy, we don’t go beyond decrying the reality of what is, and proceed to do nothing to change the problem.

15 Responses to “The Benefits of Switching From Hydrochlorothiazide to Chlorthalidone: What’s Stopping Us?”

  1. David Evans, MSN, MA says:

    I feel that CTDN truly is a superior choice. However, for those patients who also use a potassium-sparing drug, the customary choice, triamterene, is only available as a very expensive brand drug, costing over $100/month, minimum, and not covered as an affordable option by itself by most insurance policies and Part D plans. While this may seem trivial, it is important to a small, but significant group of patients with chronic hypokalemia that cannot be easily corrected by diet or KCL.

  2. Ankur Kalra, MD says:

    This is a nice post summarizing the evidence and practice patterns for prescribing thiazide diuretics. Are calculations of 6.7 fewer CV events based on 23% absolute or relative risk reduction? Although I have not read the article cited, it seems to me that 23% risk reduction in CV events in patients with heart failure is not an absolute number. Nonetheless, the argument is valid; chlorthalidone is a superior diuretic than hydrochlorothiazide, and I have seen quite a few nephrologists break this inertia and champion the change.

  3. David Kaufman, MD says:

    I could not agree more with Mr. Bergfeld. For years, I have been switching every patient I have or meet to Chlorthalidone. Clinically, in my daily experience, there is no comparison between the two drugs. 12.5mg of Chlorthalidone is hands down the winner. Interestingly, the only AE I have seen in two patients was HYPONATREMIA, not low K.

    I think there are three big reasons for the lack of uptake on this.
    1. You are right–no generic 12.5 dosage form, so have to break the pill and it’s not scored
    2. The usual and unfortunate inertia of docs and their prescribing habits. Ironically, since there is no real problem with brand and advertising we can’t even “blame” pharma.
    3. Sounds silly, but I think it’s true: it’s a big long hard to spell word vs HCTZ which is practically in our DNA.

    I thank my nephrologist consultant for educating me on this years ago.

  4. Jean-Pierre Usdin, MD says:

    In France Chlorthalidone is not availiable as a single prescription.
    The diuretic is combined in a pill with Atenolol 50mg: Tenoretic* 50/12.5.
    Probably because of economic reasons Hygroton* (was the trade name in France) was stopped on the French marked about 30 years ago.
    some patients coninue to buy it in Switzerland.

  5. Mark OBrien, MD says:

    There is little doubt that Chlorthalidone causes more hyponatremia and hypokalemia than Hydrochlorothiazide. Chlorthalidone may be more attractive in the chronic renal failure setting where hyperkalemia and co-medication with hyperkalemia provoking drugs (eg. ACEs, ARBs, Renin Inhibitors, Beta Blockers, Aldosterone Antagonists) are often present.

  6. Jose Gros-Aymerich, MD says:

    The doubt about Chlorthalidone induced hypokalemia is a pertinent one, but the doubt also comes to me about if the greater incidence of hypokalemia of CTD matches its greater efficacy, being a side-effect that would always go along with this type of diuretics. How clinically relevant is this hypokalemia?
    As we treat patients and symptoms, and not figures in a Lab chart, the issue of symptomatic hypokalemia may deserve an specific consideration, the risk of life-threatening arrythmias would be the first concern, astenia being a not much serious problem, and also the subject of Oral Potassium supplements to prevent this side effect, there are intestinal controls of the KCl absorption that may help preventing an hyperkalemia, and KCl in itself is a compound having BP lowering properties.
    A drug, initially presented in France as a vasodilator, Indapamide, as a matter of fact also HCTZ and CTD do have a direct dilating action on vessels, Indapamide now considered a Diuretic, and available in SR comps, gives also good results, the Perindopril trials used this drug, and its resuls were among the best reported.

  7. Steven Kussin, Md says:

    The issue boils down to the ease of prescribing HCTZ. If few ever heard of chlorthalidone then no one knows it’s harder abbreviation that you use. This prescribing ease has been commented on in the past as the reason this inferior med. Enjoys superior use

  8. Jose Gros-Aymerich, MD says:

    Actually, some report Oral KCl supplements not being efficacious, in cases of hypokalemia, Potassium-sparing diuretics being the most, if not the only efficacious preventive and therapeutic measure, but a dubious but safe, and very low cost preventive measure for Diuretics-induced hypokalemia, Oral K salts, is much better than nothing, or than a Trial-and-Error approach, giving a hypokalemia correcting therapy only when detected or symptomatic.

  9. Seth Martin, MD says:

    This is a really well done post on an important topic. Nicholas, I look forward to following your progress in improving on our current state of affairs. I think a comprehensive approach at multiple levels is needed to impact change, and agree with your ideas to target the EMR level, professional organization level, and policy level. I also think that a good part of our prescribing habits are formed during medical training and so you might consider engaging program directors and core teaching faculty in IM training programs, for instance.

  10. Enrique Guadiana, Cardiology says:

    Chlorthalidone is superior to hydrochlorothiazide.

    A very important difference is the extremely long half-life of 40 to 60 hours for chlorthalidone, in the other hand hydrochlorothiazide has a much shorter but wider variation in half-life, from 3 to 13 hours.

    If you use doses of chlorthalidone greater than 25 mg the benefit for BP reduction is limited. If higher doses of chlorthalidone are given, you will have a much lengthier diuretic effect, greater volume losses, and significant RAAS activation may result. Nocturia in the elderly is a frequent complain and an important reason to suspend chlorthalidone. This is long half-life is one of the explanation of the greater side effects observed in chlorthalidone vs. HCTZ.

    Chlorthalidone is not as readily available as HCTZ; there are only a few fixed-dose antihypertensive combinations that contain chlorthalidone. I discuss this in a pharmaceutical congress and the response they give me is that they prefer to combine drogues with similar half-life. At the end I believe is not a good reason.

  11. Tony Kelpie, MRCGP says:

    This is a problem in the UK too.
    Despite NICE recommending chlortalidone, it is effectively unavailable for prescription.
    Drug companies seem to be able to make the products that they want to make profits out of, and governments seem to be slow and stupid in comparison.
    Good to see a young colleague putting this case so clearly.

  12. David Powell , MD, FACC says:

    The longer half life and more robust clinical evidence base for chlorthalidone render this thiazide preferable compared with HCTZ. When compare at equipotent blood pressure lowering doses ( CTD half the dose of HCTZ), there is no difference in electrolyte effects. The efficacy of a fairly new ACEI combo with CTD may be at least partially due to the CTD. I think the paucity of combination drugs with CTD is due to an old pharmaceutical corporate deal. It would be nice to have a CTD/ spironolactone combo for resistant HTN.

  13. Umar Shakur, D.O. says:

    This is a very interesting post but I think we are confusing some important issues. Chlorthalidone has beneficial effects on important clinical outcomes in hypertensive patients (SHEP trial for instance). Thus it is an efficacious and useful treatment for hypertension.

    What is less clear, however, is whether chlorthalidone is better than HCTZ in terms of reducing CV, or other, clinical endpoints. While the analyses you present are suggestive of benefit, they are not definitive and based largely on the results of a significant protocol change in the MRFIT trial.

    Let’s consider that MRFIT not only stopped the use of HCTZ in the trial, but also decreased the maximum dose of chlorthalidone. Thus, one could interpret the change to mean that high doses of thiazides are harmful, regardless of whether the agent is HCTZ or chlorthalidone. I don’t think many of us exceed 25mg of HCTZ in routine practice today, thus it is hard to know how meaningful the MRFIT data is to lower doses of HCTZ since clearly lower doses of chlorthalidone were better than higher doses.

    Given the above, I don’t think it warrants a wholesale change in prescribing patterns of thiazide diuretics. Moreover, European hypertension experts have considered the HCTZ and CTDN debate and have come to the conclusion that there is no clear winner (see section of their recent 2013 HTN guidelines, which makes the case pretty well).

    At present, there is not clinical certainty about benefit of one thiazide compound over the other and there is some concern about the value of thiazides in general as first-line agents (lipid and glucose derangements). Given the lack of clinical clarity, I don’t think this is an area where physicians are being negligent in their duty to promoting health or protecting our patients from harm.

    My personal practice is to favor chlorthalidone for its longer half life and use it in younger hypertensive patients at the 25mg dose. I do not think providing HCTZ at optimal (i.e. lower) doses is harmful and may actually be useful for elderly patients. Also, as noted above, the combination of HCTZ/triamterene is useful for some patients in preventing hypokalemia (no one likes potassium pills).

    I applaud your enthusiasm for fighting clinical inertia, especially when it could have substantial impact on patient outcomes. We must never forget our duty to advocate for our patients best interests. I’m not sure that the HCTZ vs chlorthalidone debate is one where that is the case.

    1. http://www.esh2013.org/wordpress/wp-content/uploads/2013/06/ESC-ESH-Guidelines-2013.pdf
    2. Mortality in MRFIT http://circ.ahajournals.org/content/82/5/1616.full.pdf+html

  14. I strongly agree. I frequently use CTD 12.5 mg, a quarter of the 50 mg pill available in Spain, three times a week.
    I think that the “problem” with CTD is its low price. Why there is not a 12.5 mg pill?

  15. carol vassar, MD says:

    Nicholas Bergfeld’s post is well written and very informative for academic physicians. His frustration is clear and understandable. A comparison with the comment by Umar Shakur, D.O. Fellow in Training is also instructive. When is it appropriate for medical students to be taught the difference between epidemiological studies, case controlled trials, cohort studies and randomized controlled trials? When should they learn what can safely be concluded from the different types of studies? When should they learn about the difference between absolute benefit and relative benefit? When should they learn about meta-analyses and their limitations?

    We could have reduced his stated frustrations if he had understood all of these points.
    On the other hand, he might of wondered why we spend so much time conducting, publishing and reading these studies. He would be even more disturbed when he realized that decisions were being made on the basis of such studies. ( Are medical student today being taught about the promotion of estrogen/progesterone in the 1990’s for purely preventive purposes, rather like the treatment of HTN?)

    Dr. Shakur has already observed and survived the contradictions and inconsistencies in medical research and medical decision making. He has learned how to approach medical research- analyze it, look at the details understanding the likely weaknesses.

    Nicholas, if you read this, be reassured that what you are doing is exactly what is needed. Please continue to speak up when you become aware of those inconsistencies. If you can’t get a good explanation, look into it. There, of course is the problem. We all have time constraints, but you will fell better about yourself and will help improve medical care by bringing attention to them and helping sort them out.