Safety and tolerability of eprosartan in combination with hydrochlorothiazide.

The ideal antihypertensive drug should be effective in reducing blood pressure, but have a low incidence of adverse effects. Angiotensin II receptor blockers, such as eprosartan, are as effective as ACE inhibitors in reducing blood pressure, but lack the main adverse effect of ACE inhibitors, namely cough. Eprosartan has been shown to be well tolerated with a placebo-like adverse-effect profile. When given as monotherapy it is effective in reducing blood pressure; however, some patients require additional blood pressure control, which may be provided by combination therapy. Indeed, the combination of eprosartan and the thiazide diuretic hydrochlorothiazide has been shown to be effective in further reducing blood pressure in patients not optimally responding to eprosartan monotherapy. This article reviews the safety and tolerability of eprosartan in combination with hydrochlorothiazide from 17 studies of 1899 patients with hypertension and normotensive volunteers. Of these studies, four were controlled with patients receiving a fixed-dose combination, six were long-term, open-label, and another four were controlled studies with hydrochlorothiazide being given to eprosartan non-responders. The other three studies included healthy subjects receiving the combination of eprosartan and hydrochlorothiazide. There was a high completion rate in all studies evaluated. Most of the patients receiving eprosartan 600mg in combination with hydrochlorothiazide 12.5mg daily completed the studies, which supports acceptance of this combination therapy by patients. The most frequently reported adverse events in these combination studies were headache, dizziness, myalgia, and upper respiratory tract infection in patients with hypertension. The majority of adverse events were mild to moderate in intensity, and were not considered to be related to study treatment. The adverse event that was more common in patients receiving combination therapy compared with those receiving monotherapy was dizziness. This adverse event may be due to hydrochlorothiazide as it has previously been observed in patients taking thiazide diuretics. In healthy volunteers, the most frequently reported adverse events were headache, dizziness, and upper respiratory tract infection. However, none of these adverse events were considered related to study medication. In summary, the combination of eprosartan/hydrochlorothiazide is well tolerated, both as short- and long-term therapy, with most adverse events occurring early. The most frequent adverse events were headache, dizziness, and upper respiratory infection, which would be expected based on the safety profile of each of the components. Therefore, the combination of eprosartan with hydrochlorothiazide can be effectively and safely used in patients not adequately responding to eprosartan monotherapy.     

Fixed-Dose Combinations in the Management of Hypertension

We discuss combination therapy with angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) and thiazide diuretics in light of the independent actions of both types of agents, and the adverse effects of both agents independently and in the context of the physiologic synergy achieved in using these agents together. ARBs counteract many of the adverse events associated with the use of thiazide diuretics and have been shown to reduce the occurrence of new-onset diabetes mellitus. We also review outcome trials in patients with hypertension (such as LIFE [Losartan Intervention For Endpoint reduction in hypertension], VALUE [Valsartan Antihypertensive Long-term Use Evaluation], and SCOPE [Study on COgnition and Prognosis in the Elderly]), in which losartan, valsartan, and candesartan cilexetil were used in combination with hydrochlorothiazide. Fixed combination ARB/hydrochlorothiazide agents make sense as initial therapy for patients in whom BP is >20/10 mm Hg above goal.     

Telmisartan/Hydrochlorothiazide: a review of its use as fixed-dose combinations in essential hypertension

Fixed-dose combinations of telmisartan and hydrochlorothiazide (HCTZ) [Micardis Plus((R)), Micardis((R)) HCT, PritorPlus((R))] are available in many countries for the treatment of patients with essential hypertension. Combining the angiotensin II receptor antagonist (angiotensin II receptor blocker [ARB]) telmisartan with the thiazide diuretic HCTZ provides antihypertensive therapy with complementary mechanisms of action. In the US and EU, telmisartan/HCTZ is approved for patients whose hypertension is not adequately controlled with telmisartan monotherapy; US labelling for the fixed-dose combination also includes inadequate control of blood pressure (BP) with HCTZ monotherapy.The antihypertensive efficacy of once-daily telmisartan/HCTZ has been demonstrated in several large, randomized trials in patients with stages 1 and 2 hypertension. The addition of HCTZ to telmisartan achieved significant reductions in BP in nonresponders to telmisartan monotherapy, and the antihypertensive efficacy of telmisartan/HCTZ was similar to or significantly greater than that of various comparator agents. Moreover, in studies that used ambulatory BP monitoring, telmisartan/HCTZ provided consistent 24-hour BP reductions throughout morning, daytime and night-time periods. The BP-lowering efficacy over the entire 24-hour dose administration interval is consistent with the pharmacokinetic profile of telmisartan, which has the longest elimination half-life among currently available ARBs and a unique chemical structure. Adverse events with telmisartan/HCTZ in clinical trials were typically mild and transient, and no unexpected events occurred that had not been previously reported with either telmisartan or HCTZ. Extensive tolerability data are available for telmisartan, in particular from the ONTARGET study, the largest clinical outcomes trial with an ARB. As such, fixed-dose combinations of telmisartan/HCTZ provide an effective, rational and generally well tolerated treatment option for the management of patients with hypertension.     

Valsartan/hydrochlorothiazide: a review of its pharmacology,therapeutic efficacy and place in the management of hypertension

The combination of valsartan [an angiotensin II type 1 (AT(1)) receptor blocker] and hydrochlorothiazide (a thiazide diuretic), administered once daily, has been evaluated in the treatment of patients with hypertension in clinical trials ranging in duration from 8 weeks to 3 years. These studies showed that combination treatment with valsartan 80 or 160mg and hydrochlorothiazide 12.5 or 25mg induced significant reductions from baseline in systolic blood pressure (SBP) and diastolic BP (DBP) in patients with mild to severe hypertension. Clinical trials have demonstrated that the combination of valsartan 80 or 160mg with hydrochlorothiazide 12.5 or 25mg is significantly more effective than either drug alone. Furthermore, valsartan plus hydrochlorothiazide was effective at reducing BP in patients unresponsive to monotherapy with either agent alone. Effective BP control with valsartan plus hydrochlorothiazide was maintained in long-term studies, with reductions observed after 3 months of treatment being similar to those seen after 1, 2 or 3 years. Fixed-dose valsartan/hydrochlorothiazide showed similar BP reductions to amlodipine and to valsartan plus benazepril. Valsartan/hydrochlorothiazide also provided effective 24-hour ambulatory SBP/DBP control. Headache, dizziness and fatigue were the most common adverse events occurring in clinical trials; the incidence of these events in valsartan plus hydrochlorothiazide recipients was not significantly different to that in placebo recipients. Hypokalaemia occurred in 4.5% of valsartan plus hydrochlorothiazide recipients; valsartan attenuated the hydrochlorothiazide-associated decrease in serum potassium concentrations. CONCLUSIONS: the combination of valsartan and hydrochlorothiazide is an effective treatment for patients with hypertension. Clinical trials have demonstrated that the combination is more effective than either drug alone, and is effective in patients not responding to monotherapy with either agent. Furthermore, the adverse event profile of valsartan/hydrochlorothiazide is similar to that of placebo. Unless there are compelling or specific indications for other drugs, current data support the use of valsartan/hydrochlorothiazide when patients are unresponsive to monotherapy with either agent. Results from clinical trials evaluating the effects of valsartan/hydrochlorothiazide on cardiovascular morbidity and mortality will help to further define the role of the combination in the management of hypertension.     

Candesartan cilexetil plus hydrochlorothiazide combination: a review of its use in hypertension

The combination of candesartan cilexetil [an angiotensin II type 1 (AT(1)) receptor antagonist] plus hydrochlorothiazide (a thiazide diuretic), has been used in the treatment of patients with hypertension. The blood pressure (BP) lowering effect of various doses of this combination, administered orally once a day for 4 to 52 weeks, has been demonstrated in clinical trials. These studies showed that combinations of candesartan cilexetil 4 to 16 mg with hydrochlorothiazide 12.5 or 25 mg induced significant reductions reductions in systolic (S) BP and diastolic (D) BP from baseline in patients with mild to severe hypertension. Data from clinical trials indicated that reductions in BP induced by candesartan cilexetil 4 to 32 mg/hydrochlorothiazide 12.5 mg combinations were significantly greater than those observed after monotherapy with either drug. Treatment for 8 weeks with candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg or candesartan cilexetil 16 mg induced SBP/DBP reductions of 12.0/7.5 mm Hg and 7.5/5.5mm Hg, respectively (p < 0.05 both comparisons). Moreover, data from a randomised, double-blind, placebo-controlled, dose-finding study in 1038 patients with mild to moderate hypertension showed that the greatest reductions in SBP/DBP were achieved by candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg. Significant differences in BP reduction in favour of the combination were observed when hypertensive patients were given candesartan cilexetil 4 or 8 mg/hydrochlorothiazide 12.5 mg or hydrochlorothiazide monotherapy for 8 weeks. Additionally, greater efficacy of the combination compared to monotherapy with either drug was demonstrated by response rates to treatment. Moreover, a fixed combination of candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg demonstrated a greater antihypertensive effect than losartan 50 mg/hydrochlorothiazide 12.5 mg in two clinical trials. Candesartan cilexetil 8 mg/hydrochlorothiazide 12.5 mg showed a similar antihypertensive effect compared with that of combined lisinopril 10 mg/hydrochlorothiazide 12.5 mg. Candesartan cilexetil/hydrochlorothiazide combination was well tolerated in patients with hypertension. Combined data from placebo-controlled trials showed that most adverse events were uncommon and not serious. Patients receiving combination therapy exhibited, among other adverse events, headache (3.2 vs 5.5% for candesartan cilexetil/hydrochlorothiazide and placebo, respectively), back pain (3.0 vs 2.4%), dizziness (2.6 vs 1.2%) and respiratory infection (2.5 vs 1.4%). Moreover, 3.3 and 2.7% of patients receiving candesartan cilexetil/hydrochlorothiazide or placebo, respectively, discontinued treatment because of adverse events. CONCLUSION: The combination of candesartan cilexetil and hydrochlorothiazide (AT(1)-receptor antagonist and thiazide diuretic, respectively) is an effective treatment for patients with hypertension. Data from randomised, double-blind, placebo-controlled clinical trials showed that this combination is significantly more efficacious than either agent alone. Moreover, the combination of these two agents showed an excellent adverse event profile. Current data support the use of this combination as an alternative when monotherapy with either agent is not effective, and there are no compelling or specific indications for other drugs. However, data from large clinical trials, evaluating morbidity and mortality outcomes, are needed to determine the precise role of candesartan cilexetil/hydrochlorothiazide combination in the treatment of patients with hypertension.     

The single pill triple combination of aliskiren,amlodipine, and hydrochlorothiazide in the treatment of hypertension

Introduction: Hypertension is a leading cause of cardiovascular morbidity and mortality, and uncontrolled hypertension remains common despite the availability of several classes of effective antihypertensive medications. Combination therapy with antihypertensive agents of complementary actions has been advocated in the management of hypertension to maximize efficacy and minimize side effects.

Areas covered: This review summarizes the current data on the triple combination therapy of aliskiren with amlodipine and hydrochlorothiazide, and discusses the clinical use of single pill triple combination of aliskiren, amlodipine and hydrochlorothiazide in the treatment of hypertension and associated cardiovascular conditions.

Expert opinion: Combination therapy with antihypertensive agents of complementary actions is more effective than monotherapy in the management of hypertension. Combining an agent in renin–angiotensin blockade with a dihydropyridine calcium channel blocker (CCB) and a thiazide diuretic has plausibility in maximizing blood pressure reduction and minimizing side effects. The combination of aliskiren with amlodipine and hydrochlorothiazide has shown effective blood pressure lowering and noteworthy tolerability. The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide offers five different formulations of escalating dosages of the three agents, allowing dosing flexibility. The decreased pill burden and simplified treatment options with the single pill triple combination provide an opportunity to improve blood pressure control through improved adherence and reduced treatment inertia.     

Optimizing the Pharmacologic Treatment of Hypertension

Hypertension is a well documented risk factor for cardiovascular disease (CVD) and substantially contributes to the global burden of disease. Different drug options exist for combination therapy as part of an overall control of risk factors in order to decrease the absolute risk of CVD. Several guidelines in recent years have tried to set up recommendations to increase the proportion of subjects in acceptable BP control from high-risk groups. Some conventional drugs are still very important in modern hypertension treatment, e.g. low-dose thiazide diuretics. However, newer compounds have added to the list of useful agents to be used as monotherapy or in combination therapy for improved target organ protection, e.g. the calcium channel antagonists and ACE inhibitors. The role of β-adrenoceptor antagonists (β-blockers) has changed somewhat as a result of critical comments from recent meta-analyses. Currently, therefore, β-blockers are recommended less often for primary prevention and monotherapy, but should still be used for secondary prevention, combination therapy, and for symptom relief. Finally, the new angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) are still rather expensive, but have been increasingly documented in clinical trials for patients with essential hypertension. One controversial aspect is whether ARBs are better, worse, or equal to standard therapy with an ACE inhibitor for cardiovascular protection. BP remains poorly controlled in a large number of hypertensive patients and there is a greater need to control all relevant CVD risk factors in such patients. Therefore, different drugs are needed in order to be used in evidence-based synergistic and cost-effective drug combinations.     

The Role of Angiotensin Receptor Blocker and Calcium Channel Blocker Combination Therapy in Treating Hypertension

Hypertension remains a significant health problem, affecting approximately 30% of the US population. Of these, only 36.8% have BP controlled to recommended levels of <140/90mmHg for uncomplicated hypertension and <130/80 mmHg for patients with diabetes mellitus or renal disease. For those with uncontrolled hypertension, the risk of diabetes, renal disease, stroke, and cardiovascular disease is increased. Therapeutic options for the treatment of hypertension include several major classes of drugs: diuretics, ß-adrenoceptor antagonists (ß-blockers), ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), renin inhibitors, calcium channel blockers, and central sympatholytics, alone or in combination. Guidelines recommend thiazide diuretics as preferred first-line monotherapy. However, only 50% of patients will respond adequately to this therapy and the rest will require two or more antihypertensive agents to achieve BP goals. Clinical evidence demonstrates that some drugs have advantages when used in combination rather than as monotherapy. Drugs that block the renin-angiotensin-aldosterone system not only provide BP control but may also provide vascular protection and are metabolically neutral. This is a concise review of the safety and efficacy of ARBs in combination with amlodipine for the treatment of hypertension, with focus on the telmisartan-amlodipine combination. A MEDLINE search of the English literature from 2006 to 2009 of amlodipine in combination with ARBs revealed six publications, which are included in this review.     

ACE inhibitors,angiotensin receptor blockers and direct renin inhibitors in combination: a review of their role after the ONTARGET trial

ABSTRACT

Background: Clinical trials have shown organ-protective effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); however, cardiovascular mortality and morbidity rates, and decline in renal function remain high. In the ONTARGET trial in patients with hypertension at high cardiovascular risk, ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy, and was associated with a worse safety and tolerability profile. These results raise the question of whether ACE inhibitor/ARB, direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value.

Scope: Using PubMed and EMBASE databases, we conducted a systematic review of clinical trials published before June 2008 evaluating dual intervention with ACE inhibitors and ARBs, and compared these with trials of DRI/ACE inhibitor or DRI/ARB combinations.

Findings: A total of 70 studies met the inclusion criteria for this analysis. In patients with hypertension, ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure (BP) over monotherapy. Outcomes benefits were unclear: VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure, but at the expense of poorer tolerability. Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension, and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy, with generally similar safety and tolerability to the component monotherapies. No morbidity and mortality data for DRI/ACE inhibitor or DRI/ARB combinations are currently available.

Conclusions: ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes. DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage, but longer-term trials are required to establish whether more complete renin--angiotensin--aldosterone system control with aliskiren-based therapy translates into improved outcome benefits.     

Improving treatment adherence to antihypertensive therapy: the role of single-pill combinations

INTRODUCTION: The majority of patients with hypertension require combination therapy to achieve their blood pressure (BP) goal. Studies have consistently shown that polypharmacy and complex treatment regimens have a detrimental effect on treatment compliance, adherence and persistence (herein referred to as treatment adherence). AREAS COVERED: This paper reviews the available clinical evidence, as well as guidelines, which propose combinations of an angiotensin II receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor plus a calcium channel blocker (CCB) or diuretic. EXPERT OPINION: ARBs are associated with better tolerability compared with ACE inhibitors, and data suggest that ARB/CCB combinations may be better tolerated than CCB monotherapy. The use of true once-daily single-pill combination therapy with effective and well-tolerated agents will reduce pill burden, simplify treatment regimens and improve treatment adherence, which will, in turn, help patients to reach and maintain their BP target and achieve the short- and long-term treatment goal of cardiovascular risk reduction.     

Olmesartan medoxomil-based therapy for the management of hypertension

Contemporary practice guidelines for hypertension recommend a goal systolic/diastolic blood pressure (BP) of less than 140/90 mmHg for patients with hypertension and less than 130/80 mmHg for patients with diabetes mellitus or chronic kidney disease. Current guidelines recognize that most patients will require combination therapy to achieve these BP goals and recommend that the agents used in such therapy should have complementary mechanisms of action. Olmesartan medoxomil is an angiotensin receptor blocker approved for the treatment of hypertension as monotherapy or in combination with antihypertensive agents. It is also approved in a fixed-dose combination with hydrochlorothiazide or amlodipine. Olmesartan medoxomil-based therapy can manage hypertension across a range of patient types and has demonstrated good BP-lowering efficacy and goal attainment in individuals with stage 1 or stage 2 hypertension. The comparative antihypertensive efficacy and safety of olmesartan medoxomil, as monotherapy and as part of combination therapy, has been established in several large, randomized clinical trials. This review evaluates the chemistry, efficacy and safety of olmesartan medoxomil-based therapy and its expanding role in hypertension management.     

Economic benefits of treating high-risk hypertension with angiotensin II receptor antagonists (blockers)

Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most patients with high- or very high-risk hypertension have multiple cardiovascular risk factors with or without accompanying subclinical organ damage or established cardiovascular or renal disease. Patients with severe hypertension or with moderate hypertension and one to two additional risk factors have absolute 10-year risks of cardiovascular disease of 21-30% and 15-20%, respectively. Current European treatment guidelines recommend that antihypertensive therapy be initiated rapidly and aggressively in patients with high-risk hypertension. Most patients require two or more antihypertensive agents to achieve the strict blood pressure target of <130/80 mmHg. This article reviews the existing cost-effectiveness data on the use of angiotensin II receptor antagonists (blockers) [ARBs] in patients with high-risk hypertension. Aggressive ARB treatment of patients in the early (microalbuminuric) stages of diabetic nephropathy has a significant renoprotective effect, delaying the onset of overt (proteinuric) nephropathy. By slowing the progression of these patients to end-stage renal disease, substantial cost savings can be made. There is a paucity of cost-effectiveness data regarding the use of fixed-dose ARB plus thiazide diuretic combination therapies. Longitudinal cost-benefit studies of this attractive and efficacious first-line treatment option are needed.     

Arterial hypertension: second-line treatment. Try other single-agent treatments

(1) Reliable evidence supports the use of thiazide diuretics (chlortalidone or hydrochlorothiazide) as first-line treatment for uncomplicated arterial hypertension. (2) When patients fail to reach blood pressure targets with well-conducted treatment with thiazide diuretics, or this treatment is poorly tolerated, what are the best second-line options? To answer this question, we reviewed the available evidence, based on our standard in-house methodology. (3) We found no published trials specifically designed to evaluate second-line antihypertensive treatments in cardiovascular prevention. There were no available trials of dual- versus single-agent therapy after failure of a thiazide diuretic. (4) When the blood pressure target is not reached, inadequate drug efficacy is only one of several possible causes. Various other factors affecting blood pressure should also be investigated. (5) Dual-agent therapy carries an increased risk of adverse effects and drug interactions compared to monotherapy. (6) There is no consensus among clinical practice guidelines on second-line antihypertensive therapy. However, to minimise the risk of adverse effects, it is clearly better to select single-agent therapy with a drug that has been shown to prevent cardiovascular events in first-line treatment of otherwise healthy hypertensive patients. Possible options include: angiotensin-converting-enzyme inhibitors, angiotensin II antagonists, calcium channel blockers or betablockers. In patients over the age of 60, betablockers seem less effective that the other drugs in preventing strokes. (7) There is too little evidence to choose a specific third-line combination rather than another. However, any adverse effects that the patient experienced during prior treatments should be taken into account.     

Telmisartan/hydrochlorothiazide combination therapy in the treatment of essential hypertension

Telmisartan is an angiotensin-II receptor blocker that has demonstrated efficacy in the reduction of blood pressure in patients with hypertension. Patients with hypertension commonly require two or more antihypertensives to reduce their blood pressure to safe levels, and the choice of combination therapy should be informed by clinical trial data. Telmisartan is available in fixed-dose combination with hydrochlorothiazide (telmisartan/HCTZ) in doses of 40 mg/12.5 mg and 80 mg/12.5 mg. Telmisartan/HCTZ has been studied in a number of clinical trials in essential hypertension, for the most part using ambulatory blood pressure monitoring. It has been compared with monotherapy in full patient populations and in non-responders, and has been compared with other drug combinations. Telmisartan/HCTZ provides significantly greater reductions in blood pressure than monotherapy, and significantly increases the percentage of patients who achieve target blood pressure. The reduction in blood pressure achieved by adding HCTZ to telmisartan is greater than that achieved by adding HCTZ to atenolol, despite the fact that telmisartan and atenolol monotherapy had similar efficacy. Telmisartan/HCTZ provides significantly greater reductions than losartan plus HCTZ in 24-h mean blood pressure, primarily due to a significantly greater effect in the risky, early morning hours. Telmisartan/HCTZ is effective and well-tolerated in the elderly, diabetics and African-American patients. Ongoing studies are comparing the efficacy of telmisartan/HCTZ with valsartan plus HCTZ and amlodipine plus HCTZ in overweight, hypertensive diabetics and in patients with isolated systolic hypertension – two patient groups who are particularly at risk of target organ damage.     

Olmesartan medoxomil combined with hydrochlorothiazide improves 24-hour blood pressure control in moderate-to-severe hypertension

Abstract

Background:

Twenty-four-hour ambulatory blood pressure monitoring (ABPM) has been shown to be more reliable than conventional measurements for hypertension assessment and the associated increased risk of cardiovascular events. Olmesartan/hydrochlorothiazide combination therapy has demonstrated increased blood pressure lowering over 24 hours compared with the component monotherapies. This prespecified pooled analysis of data from two trials investigated the effects of olmesartan/hydrochlorothiazide combination therapy and olmesartan monotherapy on 24-hour blood pressure control in patients with moderate-to-severe hypertension.     

Telmisartan/hydrochlorothiazide combination therapy in the treatment of essential hypertension

Telmisartan is an angiotensin-II receptor blocker that has demonstrated efficacy in the reduction of blood pressure in patients with hypertension. Patients with hypertension commonly require two or more antihypertensives to reduce their blood pressure to safe levels, and the choice of combination therapy should be informed by clinical trial data. Telmisartan is available in fixed-dose combination with hydrochlorothiazide (telmisartan/HCTZ) in doses of 40 mg/12.5 mg and 80 mg/12.5 mg. Telmisartan/HCTZ has been studied in a number of clinical trials in essential hypertension, for the most part using ambulatory blood pressure monitoring. It has been compared with monotherapy in full patient populations and in non-responders, and has been compared with other drug combinations. Telmisartan/HCTZ provides significantly greater reductions in blood pressure than monotherapy, and significantly increases the percentage of patients who achieve target blood pressure. The reduction in blood pressure achieved by adding HCTZ to telmisartan is greater than that achieved by adding HCTZ to atenolol, despite the fact that telmisartan and atenolol monotherapy had similar efficacy. Telmisartan/HCTZ provides significantly greater reductions than losartan plus HCTZ in 24-h mean blood pressure, primarily due to a significantly greater effect in the risky, early morning hours. Telmisartan/HCTZ is effective and well-tolerated in the elderly, diabetics and African-American patients. Ongoing studies are comparing the efficacy of telmisartan/HCTZ with valsartan plus HCTZ and amlodipine plus HCTZ in overweight, hypertensive diabetics and in patients with isolated systolic hypertension - two patient groups who are particularly at risk of target organ damage.     

Fixed-Dose Combination Antihypertensives and Reduction in Target Organ Damage

Hypertension is a multifactorial disorder leading to pathophysiologic changes in target organs over time through diverse mechanisms. In addition, hypertension frequently resists control with monotherapy, necessitating combination therapy with two or more antihypertensive agents. Many currently available fixed-dose antihypertensive combinations combine drugs with different, but complementary, mechanisms of action to improve overall efficacy and tolerability. In addition, it is possible to select drug combinations whereby one drug offsets the negative effects of the other drug. Fixed-dose antihypertensive combinations may provide significant advantages over high-dose monotherapy, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to BP control. Combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients, such as those with stage 2 hypertension. The combination of a renin-angiotensin-aldosterone system-targeting agent, such as an ACE inhibitor or angiotensin II receptor antagonist (ARB), and a diuretic or calcium channel antagonist appears to provide synergy with regard to BP lowering. In addition, ACE inhibitors and ARBs have demonstrated beneficial effects beyond BP reduction, reducing cardiovascular morbidity and mortality, inhibiting development and progression of type 2 diabetes mellitus and the progression of renal disease. Preliminary studies of fixed-dose combinations have shown reductions in left ventricular hypertrophy and improvements in markers of renal function. Additional studies currently underway will compare the effects of available fixed-dose combinations on cardiovascular morbidity and mortality, and markers of renal dysfunction.     

Telmisartan 80 mg/hydrochlorothiazide 25 mg single-pill combination in the treatment of hypertension

Introduction: International guidelines emphasize the importance of blood pressure (BP) control to reduce cardiovascular risk. Telmisartan, an angiotensin II receptor blocker, provides large BP reductions and also prevents cardiovascular events in patients at high risk. The thiazide diuretic, hydrochlorothiazide (HCTZ), has a complementary mode of action, and combination with telmisartan is an established and rational treatment option for patients uncontrolled on monotherapy. A single-pill combination (SPC) of telmisartan 80 mg with high-strength HCTZ 25 mg (T80/H25) is widely available.

Area covered: Clinical data on T80/H25 SPC for the management of hypertension was identified via MEDLINE searches. T80/H25 SPC provides greater BP reductions and higher goal achievement rates in patients who cannot achieve BP goal with T80/HCTZ 12.5 mg SPC, and also as initial therapy compared with T80 monotherapy. T80/H25 also reduced BP significantly more than valsartan 160 mg/H25 combination, and demonstrated favorable tolerability in clinical trials.

Expert opinion: Patients with hypertension often do not achieve BP goal, even when treated, leaving them at increased cardiovascular risk. In part this is due to poor adherence, which can be exacerbated by treatment side effects. High BP goal achievement with SPC T80/H25, with maintained tolerability, provides a treatment option for increasing BP control.     

Therapeutic potential of angiotensin receptor blockers in hypertension

The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin II receptor blockers (ARBs) inhibit angiotensin II type 1 receptors and large clinical trials have shown that they are effective in many cardiovascular diseases including hypertension, heart failure, myocardial infarction and diabetic nephropathy. They lower blood pressure effectively, are very well tolerated and can be used as monotherapy or in combination with other drug classes for the treatment of hypertension. ARBs are particularly suitable for hypertensive patients with co-morbidities such as diabetes, microalbuminuria, proteinuria, left ventricular hypertrophy and heart failure. Unlike angiotensin-converting enzyme inhibitors, ARBs do not cause persistent dry cough. For patients in whom angiotensin-converting enzyme inhibitors are indicated but not tolerated, an ARB should be considered. Periodic monitoring of renal function and electrolytes is required in patients treated with an ARB.