Myocardial infarction and stroke associated with diuretic based two drug antihypertensive regimens: population based case-control study

Strengths and limitations

The strengths of this study include the use of a population based setting, the completeness of case identification, the validation of case diagnosis, the ascertainment of a number of potential confounding factors, and the use of the Group Health pharmacy database to obtain comparable data on antihypertensive therapy in cases and controls. All participants were members of a health maintenance organisation and thus had similar access to health care. The similarities in the clinical characteristics of the three treatment groups minimised the likelihood of important confounding by such characteristics. We used exclusion to minimise confounding by specific drug therapies for conditions such as diabetes, heart failure, coronary heart disease, and chronic kidney disease.

This study was observational, however, and the patients were not assigned at random to the antihypertensive therapy options. Unknown or unmeasured confounding factors might have existed for which adjustment was not possible. The blood pressure measurements we used in this study were obtained as part of routine care and are subject to measurement error; however, any such error would most likely be non-differential and is unlikely affect our findings. Measurement error in the assessment or estimation of other covariates and their severity might have resulted in incomplete adjustment and residual confounding. There might also have been residual confounding by indication owing to the presence of other comorbid conditions, such as chronic obstructive pulmonary disease, that could reduce the likelihood of a patient being prescribed a β blocker. This confounding is unlikely to be significant in our study given that the proportion of subjects who smoked was similar in the three treatment groups (table 1) and that the adjustment for smoking did not change the relative risk estimates. The participants in our study were almost 90% white, so our conclusions might be limited in their application to other populations.

Comparison with other studies

When additional antihypertensive therapy is needed, a patient’s comorbidities may indicate the choice of second line treatment. Large long term clinical trials have identified important major health benefits associated with β blockers in patients who have coronary disease11 or heart failure,12 and major health benefits associated with angiotensin converting enzyme inhibitors in patients with coronary disease, heart failure,13 diabetes,14 and renal failure.15 However, no trials have evaluated the influence of diuretics accompanied by different possible second line agents in terms of the ability of each regimen to prevent myocardial infarction or stroke.

Several trials of first line treatments for hypertension have included active treatment comparison groups, but the trials have generally either compared “old” drugs with “new” drugs or compared one new drug with another new drug. Examples include the International Verapamil-Trandolapril Study (INVEST)16; the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study17; the Captopril Prevention Project (CAPPP)18; the Swedish Trial in Old Patients with Hypertension-2 (STOP-2)19; the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)20; and the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial.21 Although some of these trials used diuretics as second line agents, they did not use low dose diuretics as a first line therapy and often used the β blocker atenolol as the first line agent.22

Few trials of combination therapy have used a diuretic as the first line antihypertensive agent in at least one arm of the trial. The Hypertension in the Very Elderly Trial (HYVET) used the diuretic indapamide with or without perindopril as a first line treatment in patients aged 80 years or older with hypertension, but the comparison group received placebo.23 In the recently published Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, high risk patients with hypertension were randomly assigned to receive combination therapy with benazepril plus amlodipine or benazepril plus hydrochlorothiazide.24 The primary outcome was a composite of cardiovascular deaths and cardiovascular events (with the exception of non-fatal heart failure). Blood pressure control was similar in both groups. The trial was stopped early after about three years of follow-up because the benazepril-amlodipine arm was associated with a reduced risk of cardiovascular deaths and cardiovascular events (HR 0.80, 95% CI 0.72 to 0.90). The patients in our case-control study differed from those in the ACCOMPLISH trial in several respects. Amlodipine and benazepril were rarely used as antihypertensive therapies in our study population; neither was the two drug combination of calcium channel blockers plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers. In addition, the exclusions used to control for potential confounding by indication removed most high risk patients from our study, whereas the ACCOMPLISH trial included only high risk patients. In clinical trials of antihypertensive treatments, the strategy of selecting high risk patients who have several additional risk factors is often used to increase the event rate and the power of the trial. In observational studies of antihypertensive treatment, however, the strategy of excluding patients who have additional indications for specific drug treatments is the optimal approach to control for confounding by indication for those factors.

Possible mechanism

Our findings are consistent with the renin hypothesis, which suggests that patients’ blood pressure response to different antihypertensive drugs depends on their plasma renin levels.25

Patients in our case-control study generally received a two drug regimen only if their blood pressure was not controlled on single drug therapy, usually with a diuretic (a sodium and volume reducing drug). Patients with low renin hypertension would be expected to respond to a thiazide diuretic alone and would only infrequently require a second line drug; therefore, the pool of patients in our study receiving a two drug regimen would be enriched with those who have medium or high renin hypertension. According to the renin hypothesis, those patients receiving an additional anti-renin-system drug—such as an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, or a β blocker—would be expected to respond more favourably in terms of blood pressure control and reduction in risk of cardiovascular events than those receiving a different sodium and volume reducing drug—such as a calcium channel blocker. In contrast, in the ACCOMPLISH trial, where participants were randomly assigned to a two drug regimen, we would expect a mix of high, medium, and low renin hypertension. This difference in patient populations could be responsible for the different findings for calcium channel blockers in the two studies.

Several authors have opined that the achieved blood pressure rather than the type of treatment is the major determinant of the risk of cardiovascular complications in patients with hypertension.16 18 21 This perspective implies that the most important aim of future trials would be to evaluate the association between aggressive blood pressure control and future health outcomes.26 27 From a clinical pharmacology point of view, however, it is unlikely that the major antihypertensive drug classes, with their various different targets and mechanisms of action, all have the same effect on the risks of myocardial infarction, stroke, and heart failure. For instance, in ALLHAT, patients initially randomly assigned to doxazosin had a higher risk of heart failure than those randomised to the other three treatment strategies despite achieving a similar reduction in blood pressure, and the doxazosin arm was stopped early.28 The ACCOMPLISH trial provides additional evidence in this regard.23 Such data suggest the need to consider the use of more than one strategy of blood pressure lowering in ongoing studies such as the Systolic Blood Pressure Intervention Trial (SPRINT).29

Conclusions and implications

The goal of treating hypertension is to prevent complications associated with high blood pressure. In this case-control study of relatively low risk patients, the use of diuretics plus calcium channel blockers was associated with a higher risk of myocardial infarction than the use of diuretics plus β blockers or diuretics plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers. These findings support the National Institute for Health and Clinical Excellence guidelines, which do not recommend the use of diuretics plus calcium channel blockers. A large long term trial of second line treatments in patients who are already on a low dose diuretic—as recommended by the National Heart, Lung, and Blood Institute working group7—would be required to provide a solid basis for treatment recommendations.