A new study, which I linked Sunday, showed no benefits of thiazide diuretics with respect to coronary mortality or sudden cardiac death (SCD) in the treatment of hypertension. More concerning was a signal of increased SCD attributable to thiazides. Although the trend fell short of statistical significance it was in the same direction as previous findings and had biologic plausibility based on animal models and the known arrhythmic effects of hypokalemia.
That was the bad news about thiazides. The good news was that combinations of thiazide and potassium sparing diuretics were associated with unprecedented reductions in coronary mortality (OR .59, .44-.78) and SCD (OR .60, .38-.94). This lends credence to the long held suspicion that thiazide induced hypokalemia is dangerous and brings a decades old gimmick by the pharmaceutical companies (remember dyazide, maxzide and moduretic?) into the realm of evidence based medicine.
The findings raise many questions. First, we know that placebo controlled investigation conducted in a variety of patient populations demonstrates cardiac mortality benefits for angiotensin converting enzyme inhibitors (ACEI) but not for thiazide diuretics. Why, then, did ALLHAT fail to show superiority of ACEIs over thiazides in a head to head comparison? This can be attributed to flaws in ALLHAT’s design which stacked the deck against ACEI’s. First, the ACEI was started as monotherapy in a population containing large numbers of African Americans, a group known to be resistant to ACEI monotherapy. Second, the step 2 and 3 drugs provided for in the design were arguably more synergistic with thiazide diuretics than with ACEI’s.
Although it remains to be seen whether these findings are in time to influence the soon to be published hypertension guideline update there are lessons we can apply now. Thiazide monotherapy can no longer be considered the starting treatment of choice. If not contraindicated by renal failure or hyperkalemia a thiazide/potassium sparing diuretic combination is favored. While the combination can mitigate against hypokalemia, it can still occur. Moreover, hyperkalemia and hyponatremia remain potential hazards, necessitating frequent laboratory monitoring.
Thiazides are known to work well when prescribed together with ACEI’s and angiotensin receptor blockers (ARB’s). Should this practice change? One option would be to combine an ACEI or ARB with the combination diuretic. This can be safely done with careful monitoring, although widespread adoption of the practice might result in adverse outcomes associated with hyperkalemia as has recently been observed when potassium sparing diuretics are combined with ACEI’s in the treatment of heart failure. Another option would be to continue the use of ACEI or ARB/thiazide combinations on the premise that the ACEI or ARB offsets the danger of hypokalemia. Careful biochemical monitoring is important in any case. Dr. John Oates, senior investigator of the new study, discusses the ins and outs for clinical practice in light of the new data in an interview with Medpage Today.