Initial combination therapy for rapid and effective control of moderate and severe hypertension

Moderate (grade 2) and severe (grade 3) hypertension are important public health problems associated with high cardiovascular risk. Blood pressure (BP) control becomes more difficult to achieve as hypertension progresses. Therefore, early and effective treatment is essential to prevent hypertensive urgencies and emergencies and reduce cardiovascular risk. Currently, less than 50% of patients being treated for moderate or severe hypertension in the United States achieve their BP goal as recommended by treatment guidelines. This review examines the cardiovascular risk and physician inertia associated with moderate and severe hypertension, and concludes that increased use of initial combination therapy can overcome many of the barriers to effective BP control. Furthermore, initial combination therapy with a renin-angiotensin system (RAS) inhibitor and diuretic has the potential to rapidly and effectively reduce BP across a range of baseline BPs, with a comparable adverse event profile to monotherapy.     

Initial combination therapy compared with monotherapy in diabetic hypertensive patients

Subgroup analyses were performed for the diabetic and nondiabetic cohorts from 3 randomized clinical trials that had evaluated the systolic blood pressure (SBP)-lowering efficacy and tolerability of an angiotensin receptor blocker, valsartan, alone or in combination with hydrochlorothiazide to determine when and how to initiate combination therapy in hypertensive patients with diabetes. Blood pressure reductions achieved with monotherapy were compared with combination therapy in the diabetic and nondiabetic cohorts. In addition, multivariate models were developed to predict the likelihood of the goal SBP of < 130 mm Hg being reached in a diabetic patient with monotherapy or combination therapy across the range of baseline SBP values. In 2 of the 3 trials, comparable reductions in SBP were seen in the diabetic and nondiabetic cohorts. In all 3 studies, however, combination therapy provided greater blood pressure-lowering efficacy than monotherapy. The probability of achieving goal SBP was greater for diabetic patients started on combination therapy compared with monotherapy.     

Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension

Previous studies comparing combination therapy (CT) of pulmonary vasodilators to monotherapy (MT) in patients with pulmonary arterial hypertension (PAH) report conflicting results as to whether CT is more efficacious than MT. We systematically searched the Cochrane Library, EMBASE, and MEDLINE databases for randomized controlled trials comparing CT to MT for patients with PAH. Data were pooled using the DerSimonian-Laird random-effects model. Six randomized controlled trials including 729 patients met our inclusion criteria. Follow-up ranged from 12 to 16 weeks. Compared to MT, CT resulted in a modest increase in 6-minute walk distance at the end of follow-up (weighted mean difference 25.2 m, 95% confidence interval [CI] 13.3 to 37.2). CT did not decrease mortality (risk ratio [RR] 0.42, 95% CI 0.08 to 2.25), admissions for worsening PAH (RR 0.72, 95% CI 0.36 to 1.44), or escalation of therapy (RR 0.36, 95% CI 0.09 to 1.39) and did not improve New York Heart Association functional class (RR 1.32, 95% CI 0.38 to 4.5) compared to MT. Incidence of study-drug discontinuation was similar between groups (RR 0.89, 95% CI 0.53 to 1.48). CT did not decrease the combined end point of mortality, admission for worsening PAH, lung transplantation, or escalation of PAH therapy (RR 0.42, 95% CI 0.17 to 1.04). In conclusion, this meta-analysis suggests that in PAH CT does not offer an advantage over MT apart from modestly increasing exercise capacity. However, given the paucity of good-quality data, more studies are required to define the efficacy of CT in this population before establishing final guidelines.     

Comparison of monotherapy versus combination antihypertensive therapy in elderly patients with essential hypertension

Authors sought to compare the efficacy of monotherapy versus combination antihypertensive therapy in elderly patients. Patients in this study, aged 65 to 85 years, were divided into 4 groups and entered an 8-week treatment period. First group: 22 patients, amlodipine 5 mg/d increasing to 10 mg; second: 20 patients, eprosartan 600 mg/d increasing to 600 mg twice a day; third: 21 patients, amlodipine 5 mg/d and indapamide 2.5 mg/d, increasing amlodipine to 10 mg/d; fourth: 23 patients, imidapril 10 mg/d and indapamide 2.5 mg/d, imidapril doubled to 20 mg/d. A greater drop in systolic and in diastolic blood pressure was obtained by combination of amlodipine and indapamide compared with amlodipine or eprosartan monotherapy. Imidapril and indapamide showed similar efficacy compared with eprosartan monotherapy but not with amlodipine monotherapy. Amlodipine and indapamide appeared more effective than imidapril and indapamide in diastolic blood pressure. Combination treatment with amlodipine and indapamide or imidapril and indapamide effectively reduces blood pressure in elderly patients with essential hypertension.     

Initial angiotensin-converting enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension

BACKGROUND: The Seventh Report of the Joint National Committee (JNC 7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends initial combination therapy for patients whose blood pressure (BP) is >20/10 mm Hg above goal. This study evaluated the efficacy and safety of initial combination therapy versus that of monotherapy in patients with stage 2 hypertension, who by definition meet the JNC 7 recommendation for initial combination antihypertensive therapy. METHODS: This multicenter, double-blind, 12-week study randomized 364 patients with stage 2 hypertension to fixed-dose combination therapy with amlodipine besylate/benazepril HCl (5/20 mg/d titrated to 10/20 mg/d) or amlodipine besylate monotherapy (5 mg/d titrated to 10 mg/d). RESULTS: Significantly more patients randomized to combination therapy (74.2%) compared with those randomized to monotherapy (53.9%; P <.0001) achieved the primary end point (reductions in systolic BP > or =25 mm Hg, if baseline systolic BP was <180 mm Hg, or > or =32 mm Hg, if baseline systolic BP was > or =180 mm Hg). Significantly more patients randomized to combination therapy compared with monotherapy attained BP goals of <140/90 mm Hg (61.0% v 43.3%; P =.0007) and < or =130/85 mm Hg (35.7% v 19.1%; P =.0004). Among patients with baseline systolic BP > or =180 mm Hg, combination therapy resulted in significantly greater reductions in systolic BP compared with monotherapy (-42.3 v -30.4 mm Hg; P =.001). More than 90% of patients in each group were titrated to the higher dose. Both treatments were well tolerated. CONCLUSIONS: Combination therapy was well tolerated and resulted in significantly greater BP reductions and attainment of BP goals compared with monotherapy in patients with stage 2 hypertension. This evidence supports the recommendation of combination therapy as first-line treatment in stage 2 hypertension.     

Initial and programmed combination therapy with oral drugs for severe idiopathic pulmonary arterial hypertension

A 49-year-old woman suffering from rapidly progressing right-sided heart failure assessed as World Health Organization functional class (WHO-FC) IV is described. After treatment with oxygen and diuretics, she was in WHO-FC III on admission to our hospital, as confirmed by her poor exercise tolerance in cardiopulmonary exercise testing. Upon detailed examination, she was diagnosed as having idiopathic pulmonary arterial hypertension (IPAH). Right heart catheterization (RHC) revealed severe pulmonary hypertension (mPAP = 65 mmHg) with a markedly decreased cardiac index (CI = 1.0 L/minute/m(2)), and an acute vasoreactivity test with nitric oxide inhalation did not show any response. Due to her severe condition, we decided to attempt oral combination therapy consisting of bosentan, tadalafil, and beraprost, prescribed in the same order and titrated up to their maximum respective doses, instead of intravenous (IV) epoprostenol therapy. Her clinical symptoms improved day by day, and the hemodynamic parameters recovered to nearly normal ranges about 6 months after initiation of the combination therapy. Initial/programmed oral combination therapy for severe IPAH patients is not yet fully established, and there is less evidence concerning its efficacy than IV epoprostenol therapy. However, it has tremendous advantages for PAH patients when they respond well. It is very important to further identify what types of PAH patients will respond to this oral combination therapy and should be treated with it as the first-line therapy.     

Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes

Aims: To evaluate the efficacy and safety of initial therapy with a fixed‐dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drug‐naÏve patients with type 2 diabetes. Methods: After a 2‐week single‐blind placebo run‐in period, patients with type 2 diabetes, HbA1c of 7.5–12% and not on antihyperglycaemic agent therapy were randomized in a double‐blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were up‐titrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. Results: From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were ?1.9 and ?1.4% for sitagliptin/metformin and pioglitazone, respectively (between‐group difference = ?0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [?56.0 mg/dl (?3.11 mmol/l) vs. ?44.0 mg/dl (?2.45 mmol/l), p < 0.001] and in 2‐h post‐meal glucose [?102.2 mg/dl (?5.68 mmol/l) vs. ?82.0 mg/dl (?4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [?40.5 mg/dl (?2.25 mmol/l) vs. ?13.0 mg/dl (?0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of β‐cell function (HOMA‐β) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA‐IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (?1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < 0.001 for the between‐group difference). Higher incidences of diarrhoea (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between‐group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). Conclusion: Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain.     

Antihypertensive efficacy and well-being during monotherapy and combination therapy with ketanserin

The effects of ketanserin on blood pressure and well-being were investigated in 188 patients, aged 41-82 years, with mild to moderate essential hypertension. At entry, 107 were untreated, 42 were taking the diuretic combination hydrochlorothiazide (50 mg/day) plus amiloride (5 mg/day) and another 39 were taking the beta-blocker atenolol (100 mg/day). A single-blind, 4-week placebo run-in period was followed by 12 weeks' oral ketanserin treatment at 20 or 40 mg twice a day. This regimen significantly reduced systolic and diastolic blood pressures in each group. Response rates were greater in patients aged over 60 years. Compared with placebo, sleep disturbances, daytime fatigue and overall weakness decreased during ketanserin treatment (P less than 0.05 for all), but the incidence of dry mouth and stuffy nose increased. In patients older than 60 years there was a greater reduction of complaints than in younger patients. Ketanserin proved effective and well tolerated, improving peripheral circulatory symptomatology, particularly in older patients and those with a good blood pressure response.     

Fixed-dose combination vs monotherapy in hypertension: a meta-analysis evaluation.

Fixed-dose combination antihypertensive therapy has received interest since the publication of the JNC-VI report. Relatively few head-to-head comparative studies between fixed-dose combinations and first-line monotherapies for hypertension have been published. The objective of this study was to conduct a meta-analysis of various first-line monotherapies and the fixed-dose combination of amlodipine/benazepril. The results of the meta-analysis were used to compare the efficacy and safety of the first-line monotherapies with amlodipine/benazepril. The meta-analysis included 82 studies that included 110 treatment groups (cohorts). The study compared nine different monotherapies and one combination therapy (amlodipine/benazepril). Of the 82 studies, 22 were placebo-controlled and 60 were active treatment controlled. The mean absolute decrease in supine diastolic blood pressure (BP) ranged from 9.7 to 13.3 mm Hg with verapamil showing the greatest effect and captopril the least (13.3 +/- 3.0 mm Hg; 9.7 +/- 2.9 mm Hg, respectively). When studies were weighted by sample size, atenolol, verapamil, lisinopril and amlodipine/benazepril showed the greatest BP effect. When studies were weighted by variance, amlodipine/benazepril and atenolol showed the greatest BP effect. The percentage of patients controlled on therapy ranged from 54% to 79%. Lisinopril and amlodipine/benazepril showed the greatest percent controlled. The overall incidence of adverse effects ranged from 12.1% to 41.8% with lisinopril having the lowest and nifedipine having the highest incidence. The overall incidence of adverse effects resulting in drug discontinuance ranged from 1.3% to 10.7%, with amlodipine/benazepril having the lowest and nifedipine having the highest incidence. The results of the meta-analysis indicate that amlodipine/benazepril produces above average reductions in BP with a lower than average incidence of overall side effects and the lowest incidence of adverse effects resulting in drug discontinuance. The fixed-dose combination of amlodipine/benazepril achieves its goal of effective BP lowering with a minimum of significant side effects.     

High-dose monotherapy vs low-dose combination therapy of calcium channel blockers and angiotensin receptor blockers in mild to moderate hypertension

The objectives of the study were to compare long-acting dihydropyridine calcium channel blockers (CCBs) with angiotensin II receptor blockers (ARBs) according to the ambulatory blood pressure monitoring (ABPM) profile in stage 1 and 2 newly diagnosed hypertensives and also to evaluate the efficacy of high-dose monotherapy vs low-dose combination therapy of the two drug categories among the subjects with inadequate blood pressure (BP) control after conventional low-dose monotherapy. We obtained 24-h ABPM readings from 302 subjects with newly diagnosed stage 1 or 2 essential hypertension. The study protocol consisted of initial drug treatment with a low dose of either CCBs or ARBs. Hypertensives who did not achieve BP control were randomized to high-dose monotherapy of either category of drug or low-dose combination therapy. CCBs and ARBs in low-dose monotherapy achieved BP control in 53.8 and 55.3% of the cases, respectively. However, subjects under treatment with CCBs experienced side effects more often and required that treatment be discontinued. Hypertensives who failed to control their BP with low-dose monotherapy did significantly better with low-dose combination treatment (61.6%) than with high-dose CCBs (42.8%) or ARBs (40.5%) monotherapy (P<0.05). In terms of ABPM, low-dose combination therapy exhibited better 24-h BP profile according to trough-to-peak ratio, hypertensive burden and BP variability. In conclusion, low-dose ARBs and CCBs have a comparable effect in subjects with grade 1 and 2 arterial hypertension. In hypertensives who are not controlled by low-dose monotherapy, low-dose combination therapy proves be more efficacious than high-dose monotherapy.     

A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.     

Single-agent and combination therapy of essential hypertension

Patients with mild to moderate essential hypertension were treated with beta-blockers and diuretics given separately and in combination. During single-drug therapy, the majority of patients exhibited clearly superior antihypertensive responses to either one type of drug or the other; only rarely were the beta-blockers and the diuretic equally effective in an individual patient. A poor response to diuretic therapy tended to predict a good response to a beta-blocker, and vice versa. Pretreatment renin measurements were not helpful in predicting the differing responses to single-drug treatment in this study population. These findings indicate that when one of these types of drug is ineffective as monotherapy in treating hypertension, the other type should be substituted before considering combination treatment. Combined therapy with the beta-blockers and diuretics also gave variable results, although poor antihypertensive responses could be attributed to excessive stimulation of the renin-aldosterone system by the diuretic component of the combination. The effectiveness of this form of treatment might thus be enhanced by the use of low diuretic doses.     

Fixed low-dose combination therapy for hypertension

Despite the availability of various classes of antihypertensive agents that lower blood pressure by different primary actions, the treatment of hypertension remains a difficult task. Essential hypertension has a highly heterogeneous character, so that monotherapies are often not sufficient to normalize blood pressure. This is especially true since the goal of treatment is currently to normalize both systolic and diastolic blood pressure. By combining medications acting by different mechanisms, it is possible to gain considerably in terms of antihypertensive efficacy because of synergistic impacts on the cardiovascular system. Furthermore, low doses of antihypertensive agents are generally sufficient when used in combination, which accounts for the excellent tolerability of combination products. Fixed low-dose combinations are very useful tools for treating hypertensive patients. Because of their simplicity of use, and the fact that they improve the blood pressure response rate while minimizing the incidence of adverse effects, such combinations are increasingly being considered as suitable for both second-line and first-line therapy.     

Fixed low-dose combination therapy for hypertension

Despite the availability of various classes of antihypertensive agents that lower blood pressure by different primary actions, the treatment of hypertension remains a difficult task. Essential hypertension has a highly heterogeneous character, so that monotherapies are often not sufficient to normalize blood pressure. This is especially true since the goal of treatment is currently to normalize both systolic and diastolic blood pressure. By combining medications acting by different mechanisms, it is possible to gain considerably in terms of antihypertensive efficacy because of synergistic impacts on the cardiovascular system. Furthermore, low doses of antihypertensive agents are generally sufficient when used in combination, which accounts for the excellent tolerability of combination products. Fixed low-dose combinations are very useful tools for treating hypertensive patients. Because of their simplicity of use, and the fact that they improve the blood pressure response rate while minimizing the incidence of adverse effects, such combinations are increasingly being considered as suitable for both second-line and first-line therapy.