Considerable clinical trial evidence is available in support of antihypertensive therapy to lower blood pressure (BP) as relates to the primary reduction in stroke. More recently, findings have emerged to support an important role for antihypertensive therapy in recurrent stroke prevention [1]. To this end, guidelines now suggest the provision of BP-lowering medications to both normotensive and hypertensive patients with a prior stroke [2, 3].

Two large placebo-controlled trials have provided most of the supporting evidence for this recommendation [4, 5]. In the Poststroke Antihypertensive Study (PATS) , indapamide decreased stroke rate by 29 % in a cohort of 5665 Chinese with a prior transient ischemic attack (TIA) or minor stroke [4]. Antihypertensive therapy also decreases the risk of a second stroke, a finding clearly shown by the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) , the second of these supporting studies [5]. Neither PATS nor PROGRESS specifies the level to which BP should be lowered in a poststroke/TIA population.

Core Principles of Antihypertensive Therapy

Pharmacodynamics Versus Pharmacokinetics

For most drugs and most patients, pharmacokinetic considerations are of marginal importance in that they are already reflected in the approved dose ranges and proposed dose intervals. Pharmacokinetic differences are most readily apparent in the use of certain drugs in subpopulations with reduced drug clearance. For example, a water-soluble drug mainly eliminated by glomerular filtration/tubular secretion requires dosage reduction in patients with renal impairment as is the case for the β-blocker atenolol. Such drug accumulation with possible concentration-related side effects can be expected to occur in a relevant manner when the glomerular filtration rate (GFR) drops below the 30–40-mL/min range. Alternatively, it is the pharmacodynamic properties of an antihypertensive medication that are of the greatest importance in the efficiency of BP lowering.

Dose–response Counterregulatory Effects

Dose–response effects are present for all antihypertensive drug classes but incremental reductions in BP with dose titration are most evident with sympatholytics, peripheral α-blockers, and calcium channel blockers (CCBs). A major consideration in the pharmacodynamic dose–response relationship for an antihypertensive medication is the extent to which counterregulatory mechanisms activate with BP lowering. Acute and/or chronic BP reduction can be expected to set in motion a series of mechanisms that return BP towards starting values. Reflex increases in cardiac output, peripheral vasoconstriction, and salt/water retention can arise from baroreflex-mediated activation of the sympathetic and renin-angiotensin-aldosterone (RAA) systems . These counterregulatory responses are highly dose-dependent and most regularly seen with nonspecific vasodilating drugs (e.g., hydralazine or minoxidil), high-dose diuretics, or peripheral α-blockers.

It can prove difficult to approximate the extent to which counterregulatory systems are activated with antihypertensive medications and lead to “pseudotolerance.” In that regard, a 10–20 % increase in heart rate should prompt either a lowering of the dose of the compound and/or addition of a pulse rate lowering compound—such as a β–blocker. Sodium (Na+) retention, as a factor in loss of BP control, is most easily recognized if peripheral edema occurs/worsens, although a loss of BP control can still occur with volume expansion stopping short of peripheral edema. If volume expansion is suspected a diuretic can be given, or if one is in use the dose can be increased, to effect a weight loss of 1–2 % of body weight.

Blood Pressure Monitoring and Goals

Blood Pressure Goals

Treatment of hypertension is indicated for untreated patients with an ischemic stroke or a TIA, who after the first several days have an established BP >140 mmHg systolic and/or a diastolic value >90 mmHg. In addition, resumption of therapy is indicated for patients known to be hypertensive and who are beyond the first several days of an ischemic stroke or a TIA. Blood pressure goals and/or rate and extent of BP reduction are yet to be clearly established. A systolic goal BP <140 mmHg and a diastolic BP goal of <90 mmHg would however be a sensible target and a systolic BP <130 mmHg for individuals having sustained a lacunar stroke would not be unreasonable as a target [2].

Blood Pressure Measurement

The accurate measurement of BP is a crucial issue in determining who should be viewed as being hypertensive and therein a candidate for treatment. In the patient having sustained a stroke or a TIA, there are several BP measurement considerations. First, atherosclerotic disease is not uncommon in the patient having sustained a stroke or a TIA. If one arm has sufficient plaque to lessen blood inflow more than in the other arm, then BP values will “lateralize” and the higher of the two measurements should be viewed as the value to “treat.” Second, in patients having sustained a major stroke, muscle atrophy can develop on the affected side; thus, different side-to-side BP readings will occur as a measurement artifact if the cuff used on the non-atrophied arm is unwittingly used on the larger arm. Third, the scheduling of BP measurements, in the context of timing of medication administration, is of particular importance in that trough BP readings need to be shown to be near or at goal. Blood pressure measurements obtained at the time of peak antihypertensive medication effect can engender a false sense of security as to the overall adequacy of BP control.

Home Blood Pressure Monitoring

Conventional office BP measurement yields higher BP values than home-based readings, particularly for systolic BP [6, 7]. The level of home BP suggested to best correspond to a normal clinic BP of 140/90 mmHg is ≈ 135/85 mmHg. Home BP monitoring provides a large number of readings and thus adds to the precision of BP determination in any given patient over time [7, 8]. Home BP monitoring is useful for the long-term follow-up of patients with white coat hypertension and the evaluation of treatment efficacy in patients with sustained hypertension, which is of particular importance to the patient having experienced a stroke [9].

Technical, economic, and behavioral barriers have impeded the more widespread use of home monitoring in clinical practice. Low-cost monitors with memory and systems for telephonic transmission of readings, are of some utility in overcoming these barriers. The number of clinic visits may be reduced with home BP monitoring, making it a potentially cost-effective means for the management of hypertensive patient which is of particularly important in the patient having sustained a prior stroke and who is not particularly mobile. Studies have shown that adjustment of antihypertensive treatment based on home BP measurements instead of office BP readings can lead to less intensive drug treatment, which can then be expected to reduce side effect burden and minimize instances where there might be excessive reduction in BP and/or orthostatic hypotension. The latter is of some relevance to the poststroke patient whose postural BP changes can intensify based on their level of deconditioning.

Blood Pressure Goals and the J-curve

Progressive lowering of diastolic BP to values <60 mmHg can trigger ischemic events rather than provide incremental cardiovascular protection, particularly if critical arterial stenoses exist in the coronary circulation—the “J-curve” hypothesis [10]. Many examples of the J-curve relationship between BP and cardiovascular disease events reflect reverse causality, wherein underlying disease (e.g., reduced left ventricular function, poor general health, noncompliant arteries) is the basis for both the low BP and the increased risk of both CVD and non-CVD events [11].

In the presence of limited coronary flow reserve, as is seen in coronary artery disease (CAD) , there is a J-curve relationship between treated diastolic BP and myocardial infarction, but not for stroke per se [12, 13]. Also, a wide pretreatment pulse pressure augurs an increased propensity for CVD sequelae of hypertension, which can be made more obvious by treatment [14]. Practically speaking, if systolic BP is controlled to <130 mmHg, there is marginal benefit, and even the potential for risk, in reducing diastolic BP to less than 80–85 mmHg.

There is some degree of variability in the specific target BP goal for recurrent stroke prevention, which to a certain degree reflects a variation on the J-curve theme. A meta-analysis that looked at impact of achieving tight versus usual systolic BP control on stroke prevention of randomized controlled trials found that achieving a systolic BP <130 mmHg compared with 130–139 mmHg seemed to provide additional stroke protection only among people with known vascular risk factors but not those with established or symptomatic vascular disease [15]. In point of fact, the J-curve hypothesis in the patient having sustained a stroke is untested in that most pertinent trials did not achieve recommended target systolic BP values <130 mmHg.

Need to Lower Blood Pressure Gradually

It is often recommended that BP be brought to goal gradually to avoid sudden and perhaps excessive reductions in cerebral or coronary blood flow. The rate of BP reduction is seldom a problem in the young hypertensive patient, but in the older patient with long-standing hypertension, rapid BP reduction may be poorly tolerated because of diminished cerebral or coronary artery autoregulatory ability [10, 13]. If BP drops below the autoregulatory range, symptoms of cerebral hypoperfusion such as dizziness, fatigue, and forgetfulness may arise. This is particularly the case in the elderly hypertensive patient, in whom the normal limits of cerebral autoregulation fall around a mean BP value of 100–110 mmHg. Concern about an “excessive” perceived BP drop in the elderly or the otherwise vulnerable patient should not, however, preclude attempting to reach recommended BP goals within a relatively short time (weeks rather than months) [16] since achieving rapid BP control offers significant benefits to the hypertensive patient who is at high CV risk [17]. Of note, certain antihypertensive compounds, such as ACE inhibitors, can effectively lower BP without adversely effecting regional cerebral blood flow [18].

Are the Preventive Effects of Antihypertensive Therapy Class-Specific Or Drug-Specific?

There are several drug classes used in the treatment of hypertension including diuretics, β-blockers, ACE inhibitors, ARBs, CCBs, peripheral α-adrenergic receptor antagonists, central α-agonists, aldosterone receptor antagonists amongst several other lesser used classes. There are several compounds within these drug classes and a modest degree of within class heterogeneity of a pharmacokinetic nature primarily relating to drug absorption and differing compound half-lives. Definitive evidence does not exist supporting a preferential positioning for a particular drug class in the primary or secondary prevention of stroke [19]. In that regard, the Blood Pressure Lowering Trialists’ Collaboration has reported the effects of ACE inhibitors and CCBs on cardiovascular morbidity and mortality, including stroke [20–21]. As a matter of record, these overviews revealed a 30 % reduction in stroke risk with ACE inhibitors and a 39 % decrease with CCBs compared with placebo. Nonetheless, ACE inhibitors should be strongly considered as part of a treatment plan if even to gain benefit from their cardiovascular and cardiorenal protective effects.

Drug Classes

Diuretics : First Step Therapy

Thiazide-type diuretics are important primary and adjunctive therapies in the treatment of hypertension. They are of particular utility when administered, even in doses as low as 6.25 mg of hydrochlorothiazide (HCTZ) in the form of fixed-dose combination therapy [22]. In general, loop diuretics do not reduce BP as well as thiazide-type compounds when given as monotherapy. Loop diuretics find their greatest use as antihypertensive agents when they can correct clearly evident volume expanded states. The occurrence of metabolically negative side effects such as hypokalemia, hypomagnesemia, glucose intolerance, and hypercholesterolemia is much less common with low-dose diuretic therapy (e.g., 12.5–25 mg HCTZ once daily).

Diuretics are widely promoted for the control of hypertension because they have been shown in numerous controlled clinical trials to decrease hypertension-associated morbidity and mortality rates. The thiazide-type diuretic used in both the Systolic Hypertension in the Elderly Program (SHEP) and Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was chlorthalidone and the question arises as to how this compound might differ from HCTZ [23, 24]. In that regard, the extremely long half-life of 40–60 h for chlorthalidone clearly differentiates it from the relatively short-acting HCTZ, with a half-life ranging from 3.2–13.1 h. This half-life difference is marked by a significant difference in BP reduction when chlorthalidone is compared with HCTZ [25].

These BP and existing outcomes data with chlorthalidone suggest that this compound be used with more regularity in the patient with hypertension. Thiazide-type diuretic therapy has been suggested to offer additional benefits for stroke reduction above and beyond what might be expected from BP reduction alone [26] with supporting data for this found in the PATS and PROGRESS trials [4, 5].

Angiotensin-Converting Enzyme Inhibitors : First Line Therapy

ACE inhibitors are considered a suitable first-step option in the treatment of hypertension in a wide range of patient types. Not all patients are responders to ACE inhibitor therapy but in those patients who are the dose–response curve for BP reduction is steep at low doses only to flatten thereafter at higher doses; thus, multiple dose titrations of an ACE inhibitor are seldom warranted to gain better BP control. Even modestly natriuretic doses (12.5-mg/day) of thiazide-type diuretics further reduce BP when combined with an ACE inhibitor [22]. Side effects associated with ACE inhibitors include cough, angioedema, and a distinctive form of functional renal insufficiency. . Cough and angioedema are class effect occurrences with ACE inhibitors; thus, the occurrence of either of these side effects prohibits the use of any ACE inhibitor. There is no specific level of renal function which precludes ACE inhibitor use unless significant hyperkalemia (>5.5-mEq/L) arises with their use.

The enthusiasm for the use of ACE inhibitors goes beyond their effects on BP, since they are at best comparable with other drug classes, including diuretics, ARBs, and CCBs for BP control. These drugs reduce morbidity and mortality rates in patients with HF, post MI and proteinuric renal disease; however, it would now seem that BP reduction is of more importance in reducing end-organ event rates than might be the class of drugs [27]. The data/opinions supporting ACE inhibitors in specifically reducing stroke rate have been varied [28, 29]. The Heart Outcomes Prevention Evaluation (HOPE) trial results with the ACE inhibitor ramipril showed that the benefits of lowering BP on the risk of stroke are not confined to patients with hypertension, but they also extend to individuals with BP in the normotensive range. Compared with placebo, ramipril reduced the risk of any stroke by 32 % and that of fatal stroke by 61 %. Benefits were consistent across baseline BPs, drugs used, and subgroups defined by the presence or absence of previous stroke, peripheral arterial disease, diabetes or hypertension [30].

Additional data exists from the PROGRESS trial for the ACE inhibitor perindopril in the context of secondary stroke prevention [5]. These data are important since it has been a matter of some controversy as to whether the long-term lowering of BP, in patients who have sustained a prior cerebrovascular event, reduces recurrent stroke rate comparably to the benefit observed for primary stroke rate with BP reduction. In the PROGRESS trial, BP was reduced on average of 9/4 mmHg in the active treatment group, leading to a 28 % risk reduction of major stroke. This risk reduction extended to all forms of stroke (major disabling, hemorrhagic, ischemic, or unknown), was independent of BP and diabetes status. The most beneficial effect was seen in the group being given perindopril and indapamide in which BP decreased to 12/5 mmHg.

Angiotensin Receptor Blockers : First Line Therapy

For the most part the pharmacologic differences between the several compounds in this class are of little practical consequence including their ability to prevent new-onset diabetes in at risk patients. Angiotensin receptor blockers are pulse rate neutral and do not prompt salt and water retention or SNS activation. Increasing the dose of an ARB typically does not increase its peak effect; however, it can prolong the response. Response rates with ARBs range from 40 to 70 % in Stage 1 or 2 hypertension with Na+ intake and ethnicity having some bearing on the overall effect. Although all ARBs are indicated for once-daily dosing, the effectiveness of an ARB may wane at the end of a dose interval, thereby necessitating a second dosing, which is often the case in poor to average responders. Even as there are no predictors of the magnitude of the BP reduction in response to an ARB, the coadministration of a diuretic oftentimes substantially further reduces BP [31]. Side effects are uncommon with ARBs with cough and angioedema being uncommon occurrences. ARBs can be safely used in patients with moderate to severely advanced stages of CKD with hyperkalemia being less likely than with ACE inhibitors [32].

It is this ease of use of these compounds that makes them particularly attractive candidates for the patient with hypertension. Unfortunately, there is a relative paucity of data with their use for primary or recurrent stroke prevention. In the Losartan Intervention for End-Points (LIFE) study, there were fewer strokes in the losartan-treated group than in the group treated with atenolol, which was an unexpected finding and one without an a priori specific reason for losartan to have decreased stroke rate [33]. In addition, in elderly hypertensive patients, a slightly more effective BP reduction with a candesartan-based regimen compared with control therapy, was followed by a greater reduction in the rate of nonfatal stroke [34].

Calcium Channel Blockers : First Line Therapy

Calcium channel blockers are a heterogeneous group of compounds, with distinctive structures and pharmacologic characteristics. There are two major classes of CCBs: dihydropyridines and nondihydropyridines, a subclass that includes verapamil and diltiazem. The latter two compounds reduce heart rate and cardiac contractility; whereas, the former can modestly increase heart rate in a dose-dependent manner and have little, if any, effect on contractility. The availability of CCBs in sustained-release delivery systems has improved tolerance and simplified the use of these drugs [35].

In considering CCB therapy, there are no significant differences in total major CV events between regimens based on ACE inhibitors, diuretics or β-blockers and these compounds other than for heart failure (HF), which occurs more commonly with a CCB-based regimen. Individual trials suggest a favorable effect of CCBs either given alone or together with other therapies on primary stroke prevention in diabetics [36]. A meta-regression analysis also suggests that CCBs provide more reduction in stroke rate than do diuretics or β-blockers. With this same meta-regression diltiazem compared with diuretics, β-blockers or both decreased the risk of stroke despite higher systolic pressure [19].

All patient subtypes are to some degree responsive to CCB monotherapy including elderly and low-renin, salt-sensitive, diabetic and black hypertensive patients. Calcium channel blockers have a steep dose–response curve for BP reduction, which simplifies their use since there are no reliable predictors of the magnitude of the BP reduction with a CCB. The degree to which BP drops with a CCB is a function of the pre-therapy BP; thus, the higher the BP when therapy begins the greater the fall in BP. Dihydropyridine CCBs can dose-dependently increase heart rate and in so doing diminish the accompanying BP lowering effect of these drugs. Calcium channel blockers have a mild natriuretic effect, which explains, in part, why their BP lowering effect is independent of Na+ intake.

Most CCB-related side effects are class specific, with the exception of constipation and atrioventricular block, which occur most commonly with verapamil. Calcium channel blocker use, in general, can be associated with side effects, such as polyuria, gastroesophageal reflux, and/or gingival hyperplasia; however, peripheral edema is the side effect, which most commonly influences the use of these compounds. Calcium channel blocker-related edema is positional in nature and improves when a patient goes recumbent only to recur when a patient assumes an upright position; thus in the relatively bedbound stroke patient peripheral edema may only appear when a patient becomes more regularly upright.

Beta-Blockers : Second Line Therapy

The efficacy and side effect profile of β-blockers are both compound and delivery system dependent. β-blockers reduce BP without an accompanying decrease in peripheral vascular resistance and typically exhibit a relatively flat dose–response curve, a finding that should discourage their being “over-titrated.” Beta-blockers had been first line therapy in the treatment of hypertension for a number of years. An early preferred status for these compounds was based on evidence suggesting a reduction in morbidity and mortality rates with their use in the patient with hypertension; however, more recent reviews of these data have found meager evidence to support the supposition that β-blocker based therapy, despite lowering BP, reduces the risk of heart attacks or strokes. Much of the debate on the proper place that β-blockers should have in hypertension management has focused on how effective the cardioselective β-blocker atenolol was in the treatment of hypertension and in providing specific outcomes benefits. The downfall of the β-blocker drug class (based on atenolol-related data) is premature and this drug class (and, in particular, the vasodilating β-blockers) still remains useful therapy choices.

Combined α-β-blockers are nonselective β-blockers without intrinsic sympathomimetic activity and their use has generally been reserved for the complicated hypertensive patient when an antihypertensive effect beyond that of β-blockade is desired. Labetalol, given either orally or intravenously, has been used to treat hypertensive urgencies and/or emergencies. In acutely hypertensive stroke patients, the CCB nicardipine has proven therapeutically superior to labetalol with each having been given intravenously [37]. Carvedilol has supplanted labetalol in the management of hypertension because of a cleaner side-effect profile and its being able to be given less frequently in a controlled-release delivery system. Carvedilol in its immediate release form does not adversely affect cerebral circulation parameters even as it reduces mean arterial pressure by ≈ 20 % [38]. Carvedilol has also proven more effective than metoprolol in a large heart failure study population as to reductions in stroke or fatal stroke—a finding attributed to the unique physicochemical features and not better β-blockade per se [39].

Two trials, totaling 2193 patients used the β-blocker atenolol, recording a small reduction in BP (5/3 mmHg) were neutral for secondary stroke protection [40, 41]. A recent Cochrane Database Review, relying mainly on these two trials, also concluded that there was no available evidence supporting the routine use of β-blockers for secondary protection after a stroke or a TIA [42]. In addition, a meta-analysis by Psaty et al. compared the relative benefits of high- and low-dose diuretics and β-blockers with respect to stroke and found the magnitude of effect was consistently greater with a diuretic, particularly with the low-dose regimen [43].

Aldosterone Receptor Antagonists: Second or Third Line Therapy

Although the most extensive antihypertensive treatment experience with aldosterone receptor antagonists (ARAs) exists with spironolactone, the ARA eplerenone is increasingly used because of a cleaner side-effect profile. The onset of action for spironolactone is characteristically slow, with a peak response at 48 h or more after the first dose. This may relate to a need for several days of spironolactone dosing for its active metabolites to reach steady-state plasma/tissue levels. Spironolactone and eplerenone have been used more recently as add-on therapy for resistant hypertension. The add-on effect of spironolactone occurs within days to weeks, persists for months, and is independent of ethnicity, plasma aldosterone values, and level of urinary aldosterone excretion. Hyperkalemia (>5.5 mEq/L) can also occur with ARAs and develops most typically in the setting of a reduced GFR and/or concomitant therapy with an ACE inhibitor or an ARB [44]. Aldosterone receptor antagonists are not indicated for stroke prevention; however, further studies seem warranted in stroke prevention based on emerging data with compounds in this drug class [45].

Peripheral Alpha-Adrenergic Blockers : Third Line Therapy

αl-adrenergic-blocking drugs (αl-blockers), such as doxazosin, terazosin, and prazosin, reduce BP comparable to other major drug classes. αl –blocker use has been simplified by the arrival of long-acting compounds in this class. These compounds are most effective in lowering both systolic and diastolic BPs in the upright position. α1-blockers incrementally reduce BP when combined with most drug classes and are the only antihypertensive drug class to improve plasma lipid profiles and reduce insulin resistance [46]. In the difficult-to-treat hypertensive, these compounds reduce BP significantly when used as adjunctive therapy to ACE inhibitors or CCBs. Upward dose titration of an α1-blocker can prompt renal Na+ retention, and the ensuing volume expansion can lessen any BP lowering having occurred. Thus, αl-blockers should be given with a diuretic unless doses are kept very low. In high-risk hypertensive patients, doxazosin has associated with a higher incidence of stroke and cardiovascular disease events, than was chlorthalidone [47].

First-dose hypotension or syncope although less common with doxazosin or terazosin than with shorter-acting α1 -blockers nonetheless can still occur. Orthostatic hypotension can occur with these compounds, particularly in volume-contracted patients making this a drug class to be used thoughtfully in patients having had a prior stroke and who are deconditioned. Dizziness, headache, and drowsiness are other common side effects of α1-blockers, symptoms that oftentimes can be misconstrued to represent sequelae to a cerebrovascular event.

Central Alpha-Agonists : Second or Third Line Therapy

Central α-agonists have a lengthy history in the treatment of hypertension; however, bothersome side effects have lessened the use of these compounds. Clonidine is the most commonly prescribed member of this drug class with other class members being guanfacine and alpha-methyldopa. A small dose of clonidine, in the order of 0.1–0.2 mg twice daily, adds to the BP lowering effect of most other agents and can be dependably used in this way. Dose titration of clonidine beyond 0.4 mg daily is commonly followed by compliance limiting side effects, including fatigue, sleepiness, and decreased salivary flow oftentimes described as “cotton mouth.” Increasing the dose of clonidine frequently brings on salt and water retention; thus, diuretic add-on therapy is often viewed as being complementary therapy. Clonidine is available in a transdermal delivery system that has distinct therapeutic advantages but is limited in its use by issues of cost and local skin irritation. Transdermal clonidine is particularly useful in the management of the labile hypertensive patient, the hospitalized patient who cannot take medications by mouth, and the patient subject to early morning BP surges. At equivalent doses, transdermal clonidine is more apt to precipitate salt and water retention than does oral clonidine [48]. Clonidine is also useful second line therapy to aid in smoking cessation an important consideration in the patient with a prior stroke who remains a smoker.

Conclusions

Treatment of the patient with hypertension following a stroke begins at the time of a stroke. Typically, BP is allowed to permissively remain elevated in the immediate peri-stroke period. However, it is not uncommon for there to be a carryover effect such that the decision to either implement or proceed with aggressive chronic antihypertensive therapy is slow to occur. Blood pressure values in excess of national guidelines are common after stroke and/or TIAs. For this reason, long-term BP reduction in the poststroke patient should be in the hands of physicians comfortable with varying therapeutic goals and the numerous treatment options for BP control.

Lifestyle modifications should be considered in the treatment of hypertension including weight loss, limiting alcohol use, aerobic exercise, and consumption of a diet rich in fruit and vegetables. Clinicians should carry out an individualized selection of drug(s) process, based on demographic characteristics and comorbidities (cardiovascular disease, diabetes mellitus, and other chronic illnesses) among diuretics, ACE inhibitors, ARBs, or CCBs mindful of the frequent need for multidrug combination therapy to effect hypertension control. An optimal drug regimen to achieve the recommended level of BP reduction is unclear in that head-to-head regimens have not occurred; available data would suggest that the combination of a diuretic and an ACE inhibitor or a CCB and an ACE inhibitor are useful.