Hypertension has traditionally been defined by the level of BP Hypertension has traditionally been defined by the level of BP. The risk of cardiovascular (CV) events occurring with a given level of BP, increases with the number of concurrent risk factors. Many patients have a variety of risk factors including, obesity, dyslipidemia, cigarette smoking, and glucose intolerance. Optimal BP thresholds and targets for individual patients depend on baseline overall CV risk; therefore, they may need to be defined even when the patient has a BP level that is considered within the “normal” range. Results of recent clinical trials have led to a lower threshold for both optimal BP levels and initiation of therapy. While some trials have recruited patients with high BP, others included those with only modestly elevated BP or with no BP entry criteria at all.

These figures show the prevalence of hypertension in Canada (Canadian Heart Health Survey.CHHS) and in the USA (Third National Health and Nutrition Examination Survey, NHANES III). To determine the proportion of hypertensive patients who are being appropriately managed, according to the 2001 Canadian Hypertension Recommendations, data from the CHHS were used. Patients not recommended for therapy were excluded from the analysis. Results showed that 25% of hypertensive Canadians in CHHS would not receive drug treatment based on the 2001 Canadian recommendations. Only 16% of hypertensives were treated and had their BP controlled to <140/90 mm Hg.

Guidelines for managing hypertension are widely available Guidelines for managing hypertension are widely available. The Canadian recommendations are updated annually. Recommendations for initiating drug therapy for hypertension differ between countries. Based on the 2001 Canadian recommendations, the British Hypertension Society (BHS) Guidelines, and the World Health Organization/International Society of Hypertension (WHO/ISH) Guidelines, drug therapy is not recommended for “low risk” patients. On the other hand, the 6th report of the Joint National Committee (JNC-VI) in the US recommends drug treatment if lifestyle modification is unsuccessful. It is unclear whether this more aggressive approach accounts for the better BP control rate (<140/90 mm Hg) in the US. However, there is substantial evidence that the existing guidelines and recommendations do not achieve their objectives. This may be because some healthcare deliverers (ie, physicians) are either unfamiliar with existing recommendations or are unconvinced of their validity. Consumers (ie, patients) also play an important role in BP control. Poor compliance is the major factor, due to unawareness, side effects of drugs, inconvenient dosing schedules, and the frequent need for multiple drugs.

Several large-scale clinical trials have demonstrated that many patients require 3 or more drugs to achieve optimal BP control. For example, in the Hypertension Optimal Treatment (HOT) study, to achieve a target DBP of  90, ≤ 85, and ≤ 80 mm Hg, 63%, 68%, and 74% of patients, respectively, needed to use multiple drugs. INSIGHT = International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment LIFE = Losartan Intervention For Endpoint reduction in hypertension study

Given that a high dose of a single agent may be associated with unacceptable side effects and the use of multiple agents is associated with the risk of poor compliance, an alternative approach may be to utilize fixed low-dose combinations. Combining agents that act via different mechanisms enhances antihypertensive efficacy. Low doses of agents are generally sufficient when used in combination, explaining the excellent tolerability of combination products. Fixed-dose combinations simplify treatment regimens by reducing the number of tablets, increasing compliance, and lowering the price as compared to extemporaneous combinations. Since most patients (other than those with mild elevations of BP) require multiple agents to achieve optimal BP control and given the advantages of fixed-dose combinations, various formulations are being examined in clinical trials.

Combination therapy for hypertension started in the 1950s Combination therapy for hypertension started in the 1950s. The SER-AP-ES combination was a popular antihypertensive agent in the 1960s. In the 1970s, potassium-sparing diuretics in combination with a thiazide was popular. For both, the combination was based on complementary component effects either to enhance antihypertensive effects and/or to minimize hypokalemia. Potassium-sparing is better achieved by combining spironolactone or amiloride with a thiazide diuretic than with potassium supplements alone. In the 1980s, although not popular, thiazide diuretics were combined with “newer agents” such as ß-blockers. The most recent combination is an angiotensin-converting-enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) with a thiazide or an ACEI and indapamide, an indoline derivative of chlorosulfonamide that has both antihypertensive and diuretic properties.

The status of fixed as compared to extemporaneous forms of combination therapy from the perspective of current guidelines/recommendations for hypertension management reveal differences. The fixed approach is considered in JNC-VI, the BHS guidelines for hypertension management, as well as, the WHO-ISH guidelines, but only the JNC-VI clearly recommends fixed-dose combinations in low doses as initial therapy. Both the BHS and the WHO/ISH guidelines consider fixed-dose combinations as a valid approach when monotherapy is ineffective, individual drug components are appropriate, and there are no major cost implications. In the Canadian recommendations (2001), the old approach of replacing ineffective monotherapy with another drug from a different class was updated to include the alternative option of adding a second drug from a class with a complementary antihypertensive mechanism to the first drug. Fixed-dose combinations have not yet been addressed in the Canadian recommendations, presumably because they are heavily based on clinical evidence.

This slide gives an example of dose-ranging studies that need to be conducted to formulate fixed-dose combination therapy. A multinational, randomized, double-blind comparison of perindopril (Per) and indapamide (Ind) versus placebo was performed using a 7-way parallel-group design. A group of 438 patients with supine DBP between 95 and 114 mm Hg (Europe) and between 95 and 109 mm Hg (Canada) were randomized to 8 weeks of treatment using fixed-dose combinations. The combinations explored the impact of doubling Per 2/Ind 0.625 mg up to Per 8/Ind 2.5 mg, and increasing the doses of Per from 0 to 8 mg in combination with a fixed-dose of Ind at 1.25 mg daily. A 4-week placebo period preceded the randomization. The primary efficacy outcome was the change in clinical supine DBP, 24 hours after the previous dose. Secondary outcomes included the changes in supine SBP, standing BP, ambulatory BP, and response rate. The 7 groups of patients were comparable in their baseline BP. The effects of doubling the dose of Per and Ind resulted in a progressively greater decline in SBP and DBP (all p <0.05 vs placebo). Increasing Per with a fixed-dose of Ind was also associated with a progressively greater decline in SBP and DBP (all p < 0.05 vs placebo). Similar patterns of dose-dependent decline in BP were observed in standing BP and 24-hour ambulatory BP.

For this trial, response rates based on pre-defined criteria are shown above. For both combinations, the percentage of responders increased in a dose-dependent manner. Hypokalemia (serum potassium level < 3.4 mmol/L) at week 4, was most frequent in the Per 8/Ind 2.5 mg group, occurring in 8 of 64 patients. The incidence of hypokalemia at any time varied between 0% and 4.6% for all combinations, except for Per 8/Ind 2.5 mg that had an incidence of 9.7%. Both 2 mg and 4 mg of Per, as well as 1.25 mg and 2.5 mg of Ind, significantly reduce placebo-corrected supine BP. Compared with previous studies, the combination of Per and Ind produces a greater decline in BP. Furthermore, both Per and the combination of Per and Ind have been demonstrated to reduce the incidence of recurrent stroke, a beneficial effect thought to be related to BP control. Balancing the antihypertensive and hypokalemic effects, together with the observation that the addition of 0.625 mg of Ind to 4 mg Per did not substantially increase the response rate, suggests that Per 2/Ind 0.625 mg and Per 4/Ind 1.25 mg daily are likely the optimal combinations for clinical use.

Previous studies reveal that low-dose indapamide is efficacious in the treatment of patients with mild to moderate hypertension, including those with impaired renal function because of the reduced impact on metabolic and electrolyte parameters. In addition, Ind reduces LV hypertrophy and micro-albuminuria, and has no adverse effects on the lipid profile, unlike other thiazide diuretics. A logical combination is therefore that of indapamide and perindopril.

In summary, fixed, low-dose combinations are potentially powerful tools for treating hypertensive patients. Because of their simplicity of use and the fact that they improve the BP 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 in patients with hypertension.